Advances in hybridized nanoarchitectures for improved oro-dental health

Abstract

On a global note, oral health plays a critical role in improving the overall human health. In this vein, dental-related issues with dentin exposure often facilitate the risk of developing various oral-related diseases in gums and teeth. Several oral-based ailments include gums-associated (gingivitis or periodontitis), tooth-based (dental caries, root infection, enamel erosion, and edentulous or total tooth loss), as well as miscellaneous diseases in the buccal or oral cavity (bad breath, mouth sores, and oral cancer). Although established conventional treatment modalities have been available to improve oral health, these therapeutic options suffer from several limitations, such as fail to eradicate bacterial biofilms, deprived regeneration of dental pulp cells, and poor remineralization of teeth, resulting in dental emergencies. To this end, the advent of nanotechnology has resulted in the development of various innovative nanoarchitectured composites from diverse sources. This review presents a comprehensive overview of different nanoarchitectured composites for improving overall oral health. Initially, we emphasize various oral-related diseases, providing detailed pathological circumstances and their effects on human health along with deficiencies of the conventional therapeutic modalities. Further, the importance of various nanostructured components is emphasized, highlighting their predominant actions in solving crucial dental issues, such as anti-bacterial, remineralization, and tissue regeneration abilities. In addition to an emphasis on the synthesis of different nanostructures, various nano-therapeutic solutions from diverse sources are discussed, including natural (plant, animal, and marine)-based components and other synthetic (organic- and inorganic-) architectures, as well as their composites for improving oral health. Finally, we summarize the article with an interesting outlook on overcoming the challenges of translating these innovative platforms to clinics.

Graphical abstract

Introduction

Over the past few decades, it has been increasingly recognized that oral health always plays a crucial role in expediting the overall health of humans [1]. Although oral diseases are majorly preventable, several dental/oral-related diseases pose a major health burden in many countries, affecting lifestyle, discomfort, and even death [1]. According to World Health Organization (WHO) statistics, the Global Oral Health Status Report in 2022 stated that oral-related diseases have significantly affected approximately 3.5 billion people globally, accounting for 3 out of 4 people in middle-income countries [2]. Along this line, some of the most common diseases that impact oral health include cavities (tooth decay), gum-related (periodontal) diseases, and oral cancer [3]. In this context, tooth caries affected a total of 2 billion people of adults with permanent teeth and 0.5 billion of children with temporary teeth [4]. Considerably, the statistics indicated that over 40% of adults reported pain last year, and over 80% of people had at least a cavity by the age of 34 [5]. The predominant reasons for the increased rate of dental-related disorders could be untreated dental caries in permanent teeth because of expensive treatment, no health insurance coverage, and insufficient infrastructure in most low- and middle-income countries [6].

Typically, dental-related issues with dentin exposure often increase the risk of developing oral diseases [7]. Prior to exploring dental-related ailments and their treatments, it is imperative to understand the tooth hierarchical structure, including periodontal (superficial), orthodontic (bone-associated), and endodontic layers (dentin-pulp). Briefly, the superficial periodontal components of the tooth are predominantly made of the toughest enamel tissue with hierarchical layers. The middle orthodontic layer is composed of a bony layer offering physical support. The lower or deeper endodontic layer is composed of the dentin. The periodontitis or dental caries caused by a microbial infection on the top layers of the tooth may influence the dentin-pulp complex in the endodontic layer. In this framework, several dental-related disorders include gums-associated (gingivitis or periodontitis, and inflammation), tooth-based (dental caries, root infection, enamel erosion, tooth sensitivity, erosion, decay, and edentulous or total tooth loss), as well as overall buccal/oral-related ailments (dry mouth, bad breath, mouth sores, oral cancer, and miscellaneous bacterial infections) [8]. These highly painful oral-related disorders often result in toothaches and dental emergencies. Other prominent oral conditions include noma (pediatric gangrenous disease), oro-facial clefts, and oro-dental trauma [9]. These oral diseases, including dental caries (tooth decay), periodontal diseases, and oral cancers, are often caused by a range of modifiable risk factors [10], such as sugar intake, alcohol, and tobacco consumption, as well as poor hygiene, among others [11, 12]. The prevalence of oral-based ailments has been growing with urbanization and changes in the living conditions of the patients, such as inadequate exposure to fluoride, high sugar, alcohol intake, and insufficient access to health services.[13] Although general considerations are specified, the main reasons and available treatment options for dental problems are elucidated in the further sections (Sect. "Oral ailments").

Notably, dentists often prescribe various conventional formulations to improve oral health with preventable therapeutic outcomes in the early stages. Along this line, several established treatment modalities for multiple kinds of ailments include conventional dental care formulations, such as antibiotic solutions, mouthwashes, and calcium constructs, among others. Regarding early caries and bacterial infections, various antibiotic solutions and mouthwashes are widely used to deliver antimicrobial agents. Despite the availability, these established conventional treatment modalities suffer from several limitations. Predominantly, the biofilms created by the bacterial colonies and acquired antibiotic resistance as defense mechanisms result in poor therapeutic outcomes, leading to further progression of oral diseases towards the loss of teeth and damage of gums [14]. In terms of designing the mouthwashes, formulating these traditional dosage forms with conventional drug formulations is highly challenging due to the hydrophobicity of the antimicrobial agents. Regarding the mineralization of hard tissues, several irrigants are applied, such as sodium hypochlorite, ethylenediaminetetraacetic acid (EDTA) [15], and chlorhexidine (CHX), which can pose compatibility-associated risks due to the accidental extrusion [16]. Moreover, the eventual sealing agents filling the gaps between the filler and root dentine may pose to bacterial growth and result in the poor remineralization of the tooth, requiring the encapsulation of antimicrobial agents towards improved remineralization [17, 18]. Towards the reconstruction of damaged tissues, biomimetic conventional scaffolds have been applied, posing various limitations in terms of lack of regeneration abilities. Although various stem cells can be predominantly utilized, the lack of odontogenic potential results in the deprived regeneration of dental pulp cells, leading to recurrence and dental emergencies [14]. Considering these limitations, it is required to explore various innovative nanoarchitectures as proven constructs towards improved drug delivery, remineralization, and regeneration abilities. In addition to oro-dental conditions, several reports suggested that various oral diseases (for instance, tooth loss) were associated with psychological disorders, such as depression. The reasons could be past periodontal inflammation or autonomic nerve imbalance due to oral-related pain, stress, and discomfort, increasing symptoms of depression [19]. In addition, as stated in the cohort studies, poor oral hygiene, i.e., oral microbiota, could be associated with systemic inflammation and bacteremia, resulting in the development of gastrointestinal cancers, such as oral, esophageal, gastric, and pancreatic, among other [20]. Moreover, the inflammation in the gums leads to various systemic diseases based on cardiovascular diseases, such as atherosclerosis [21]. Considering these attributes, every human being would be required to maintain healthy oro-dental conditions to have a fresh breath and boost confidence [22].

Since the advent of nanotechnology, several advancements have been evidenced toward generating various nanoarchitectures within the size range of 1–100 nm in one of the dimensions [23]. Specifically, these ultrafine structures offer various advantages, such as convenient synthesis, stability, ease of scale-up, and tailorable morphological (size, shape, and structure), as well as physicochemical (mechanical, electronic, optical, and magnetic) characteristics [24, 25]. These nanoarchitectures gained enormous interest from researchers due to their predominant advantages, such as high surface-to-volume ratio and abundant surface chemistry, facilitating the loading of diverse guest molecules either through encapsulation in the framework or immobilization on the surface [26]. In addition, these ultrafine structures encapsulated with guest species facilitate the ease of conveyance by not only crossing the typical biological barriers in the body but also enabling the responsive (ultrasound- [27], magnetic- [28], and photo-[29]) release towards improving the therapeutic efficacy in vitro and in vivo.[30] In addition to encapsulation and delivery abilities, the convenient tailorable surface substantially improves the intrinsic features of biocompatibility and thermal, as well as colloidal stabilities [31]. These ultrasmall-sized nanoarchitectures are often synthesized using diverse sources and precursors, including polymeric (chitosan, and alginate), gold (Au), silver (Ag), titanium, calcium phosphates (hydroxyapatite), zinc oxide (ZnO)-based quantum dots (QDs), MXenes, rhodium, silica (mesoporous silica and amorphous silica), and palladium-based nanoconstructs [32,33,34]. These nanoarchitectures with tunable advantages and multiple precursors are of particular interest in various fields of science and technology, including but not limited to adsorption, agriculture, engineering, energy, environment, and biomedicine-related fields [35,36,37]. Apart from the diverse sources, substantial technological advancements have changed medical care and integrated it with dentistry [38]. More importantly, developing innovative anti-microbial, evaluating genomics, and evolving robotics and artificial intelligence can transform the clinical care of dental-related diseases [39].

Despite several reviews on dental-related diseases and exploring various nanostructured components [40, 41], this review presents a comprehensive overview of different nanoarchitectured components and their hybridized composites for improving oro-dental health (Fig. 1). In this review, we first discuss various bothering dental-related diseases, highlighting detailed pathological circumstances and their effects on human health and deficiencies with the currently available conventional therapeutic modalities. Further, the importance of various nanostructured components and their predominant roles in addressing severe dental-related issues are emphasized, highlighting substantial anti-bacterial effects, remineralization, and tissue regeneration abilities. This section provides a discussion of how the materials act to improve oral health. In addition, a brief note on different synthesis approaches of nanostructured components and their hybridized composites is provided, exploring the impact of various synthesis conditions on their morphological and physicochemical properties. Further, various hybridized nanocomposites based on numerous precursors as therapeutic solutions are discussed, including nature-based (plant-, animal-, and marine-derived) and synthetic (organic- and inorganic-) precursors for improving oral health. Finally, we summarize the article with an interesting outlook, focusing on overcoming the challenges of translating these innovative platforms into clinics.

Fig. 1

Schematic displaying various dental-related (gum-/tooth-/oral or buccal-based) ailments and appropriate therapeutic solutions based on natural (plant/marine/animal-derived) and synthetic (organic–inorganic-/organic–inorganic-based) nanoarchitectures

Oral ailments

The major cause of various dental-related disorders is the growth of microorganisms in the oral cavity [42]. The oral cavity acts as one of the predominant gateways for over 700 bacterial species, connecting the external environment with the gastrointestinal tract [43]. Notably, microbiome dysbiosis plays a crucial role in oral hygiene, in which the imbalance leads to various oro-dental diseases. The sequential progression of dental health issues and eventual tooth loss can be explained in several stages [44, 45]. Initially, the microbial imbalance in the oral cavity results in the bacterial biofilm formation, leading to the formation of caries or plaques on the tooth surface [46, 47]. The untreated plaques lead to pulpitis and apical periodontitis, resulting in local inflammation [48, 49]. Further, the inflammatory responses throughout the oral cavity result in highly complex gum-related diseases, such as gingivitis, periodontitis (mild or advanced), and peri-implantitis [50]. In addition to dental issues, several reports indicated that microbial dysbiosis inducing systemic inflammation would result in other complex ailments such as diabetes, risk of cancer, and myocardial infarction [49]. Several other predominant direct reasons for the cause of these dental-related disorders include sugar intake [51], alcohol [52], and tobacco consumption [53], as well as poor hygiene, among others. Apart from direct reasons, other external factors may influence dental health. For instance, the patients subjected to radiation therapy for head and neck cancers result in long-term adverse effects of mouth dryness, swallowing dysfunction, and altered taste [54, 55]. Although it has a minor influence on dental health, research remains to explore patient compliance after head and neck cancer therapy [56].

Considering these complications, several dental-related disorders have been broadly categorized into three categories, including gums-related, teeth-related, and miscellaneous diseases in the buccal cavity (Fig. 2). The gums-associated conditions are predominantly encountered, including gingivitis or periodontitis, referring to inflammation in the gums. Tooth-based ailments include dental caries, enamel erosion, root infection, tooth sensitivity, erosion, decay, and edentulous (total tooth loss). Lastly, various miscellaneous diseases affecting the oral cavity, other than gums and teeth, include dry mouth, bad breath, mouth sores (canker, cold, and thrush), oral cancer, and miscellaneous bacterial infections, eventually distressing gums and teeth, resulting in toothaches and other oro-dental ailments. This section presents discussions relevant to these diseases, highlighting predominant causes, severity, and treatments available for these ailments.

Fig. 2

Schematic illustrating various oral-related (gum-/tooth-/buccal-based) ailments

Gums-related disorders

Several gums-related ailments, referred to as periodontal (gum) diseases, are characterized by the systemic inflammation of the tissues surrounding teeth, such as gingiva, periodontal ligament, and alveolar bone [57]. Often, the symptoms of various periodontal diseases include bleeding or swollen gums (gingivitis), pain, and sometimes bad breath, even leading to tooth loss in several instances. The severity of periodontal diseases can be statistically estimated [58]. Overall, 1 billion cases have been recorded, accounting for 20% of the global population [59]. The predominant reasons include poor oral hygiene and extensive tobacco usage, causing periodontal diseases. Among various periodontal diseases, gingivitis is the early stage of gum-related ailments, often caused by bacterial infection [60,61,62]. This mild periodontal ailment is initially caused by bacterial film accumulated on the teeth surface adjacent to the gums, affecting the supporting structures of the teeth [63]. The common symptoms include redness, swelling, and bleeding gums. Different from gingivitis in terms of infection and affected structures, periodontitis is the advanced stage of gums-related diseases, involving the loss of the alveolar bone and leading to tooth loss [49]. More often, untreated gingivitis results in periodontitis, manifested by infected gum pockets and shrinking of gums, leading to the damage of bone and surrounding tissues [64]. The periodontitis condition can trigger inflammatory responses throughout the body, resulting in various metabolic disorders [65]. In addition to conventional inflammatory diseases in gums, receding gums can lead to other dental issues, exposing the delicate root of the tooth and making it susceptible to damage, requiring special care in terms of cleaning and brushing [66]. In addition to poor brushing, the other common reasons for various periodontal diseases include extensive tobacco usage, diabetes, and pregnancy [67]. Some common solutions for periodontal diseases include appropriate cleaning, regular brushing, and flossing. Notably, several invasive procedures that use dental materials for the restoration of caries or the placement of implants require incorporating anti-microbial agents to avoid undesirable gum damage.

Tooth-related illnesses

In addition to gums, tooth-related disorders have been evident due to microbial infection and subsequent undesirable effects on the surface of the tooth and root canal, such as dental caries, cracked teeth, enamel erosion, root infection, and edentulous (tooth loss). Among various dental-related ailments, the dental caries condition, often referred to as tooth decay, has emerged as the most prevalent tooth-related ailment [68]. Considering the etiology, the microbial imbalance in the oral cavity results in bacterial biofilm formation on the surface of the tooth, leading to dental caries [69]. Further, the formed plaques on the tooth surface convert the consumed sugars to acids, leading to tooth demineralization. In addition, the acids work on the soft dentin layer and permanently damage the enamel [70]. Simultaneously, the induced caries destroy the tooth progressively [71]. The symptoms of tooth decay include bad breath, spots on teeth, and unpleasant taste. Common sources of tooth decay include excessive sugar consumption, inadequate fluoride exposure, and unremoved plaque promptly. Further, these tooth decay conditions often cause extreme pain [72]. In some instances, excessive infection may lead to tooth loss. More often, the condition of dental caries is treated by filling restoration followed by dental implants to address the complete tooth decay [73]. Nevertheless, the lack of anti-caries properties of the fillers may result in secondary caries, requiring new anti-caries materials [74]. In addition, common suggestions from dentists include appropriate brushing, flossing, and scraping of plaques.

Several minor ailments are commonly seen, such as cracked teeth, bruxism, enamel erosion, and root infection. The broken or cracked teeth are obvious, manifested due to injuries and mouth piercings. These conditions can be treated with veneer, crowning, capping, or tooth-colored filling. Similarly, bruxism, called teeth grinding, often occurs in sleep, causing teeth damage and may lead to severe pain and headache [75]. Typically, bruxism is caused by sleeping disorders and other neurological conditions such as anxiety [76]. Further, enamel erosion happens due to the long-term high consumption of sugars and acidic beverages. Rarely, frequent brushing and often cleaning with pressure for a long time may result in the loss of enamel [77]. The erosion of enamel usually leads to sensitive teeth being more susceptible to cracks [78]. The major treatment options include the restoration of enamel and a significant reduction in damage by avoiding sugars and acidic foods. The root canal, i.e., the basement of the tooth, can be infected with bacteria, resulting in tooth cavities, damaging the nerves, and ultimately developing abscesses. The pathological manifestations include chronic toothache and a swollen face around the infection [79]. Typically, the root canal is applied to treat root infections due to minimal pain with the safe use of local anesthesia [80]. The major issue with these toot-related ailments is their sensitivity [81], hampering the food intake of extreme temperatures, such as hot and cold foods and drinks. The sensitivity increases in the case of dentin exposure due to the wearing of enamel. The sensitivity results in pain as the nerves in deeper dentin are exposed to the consumed substances. More often, tooth sensitivity can be caused by tooth decay, gum diseases, root infection, cracked tooth enamel erosion, and receding gums [82]. These aforementioned tooth-related ailments can be treated with specific strategies of tooth caring and remineralization, crowning, capping, and other approaches [83]. The condition of edentulous or total tooth loss is generally the eventual point of an oral disease. In this context, several dental caries, advanced periodontal diseases, and other diseases often result in edentulous conditions. As per statistics, the average prevalence of total tooth loss for people 60 years or older would be 23% [95] while for 20 years or older, it would be 7%. It should be noted that the edentulous conditions would be psychologically distressing and traumatic from social and functional points of view.

Miscellaneous diseases

In addition to specific tooth- and gums-based ailments, several other diseases in the buccal cavity influence oral hygiene, such as oral cancer, dry mouth, and bad breath. Oral cancers, the most dreadful oral ailments, are often evident in the buccal cavity and gums, such as cancer on the lips, oropharynx, and other mouth parts [84, 85]. These cancers are commonly seen in older adults and more dreadful in men than women, varying according to socio-economic status. Excessive usage of tobacco, alcohol, and betel quid are the leading sources of oral cancers in the buccal cavity [86]. In addition, human papillomavirus infections are crucial in young people affected with oral cancers in some areas, such as North America and Europe [87]. Surgical removal is the current initial choice of treatment. In addition, radiation therapy, molecularly-targeted chemotherapeutics (doxorubicin, adriamycin, and cisplatin, among others), and utilization of immune checkpoint inhibitors have been applied for advanced cancers [88, 89]. Several other commonly seen oral disorders include dry mouth and bad breath [90]. Although commonly seen in older people, any individual can be affected by dry mouth. Several reasons include various diseases, such as HIV/AIDs [91], nerve damage, salivary gland disease, and diabetes [92], as well as medications for cancer therapy [93]. The best choice over a dry mouth is consuming water frequently and avoiding alcohol, tobacco, caffeine, and high-sugar foods. To this end, one of the most common dental problems is bad breath from the oral cavity [94]. This highly distressing condition is caused by poor oral hygiene, dry mouth, certain spices (garlic and onion), and oral cancer [95]. Maintaining hygiene and reducing the intake of certain spices can improve the quality of breath.

Several other common ailments in the oral cavity are related to the tooth, gums, and oral cavity, and their effects are discussed. In this context, oral cavity ailments include oro-dental trauma, noma, and oro-facial clefts. Oro-dental trauma refers to damage to teeth, the mouth, and the oral cavity during injuries. Recent statistics estimated that over a billion people were affected by oro-dental trauma, with the prevalence of around 20% being children [96]. Traumatic conditions can be caused by many other factors, including injured teeth due to accidents [97] and inappropriate teeth alignment. The treatment options include filling restoration, capping, and teeth arrangement, which result in facial and psychological complications towards quality of life. Noma starts as a soft tissue lesion (a sore) of the gums, leading to acute necrotizing gingivitis and destroying all the soft tissues in the oral cavity initially and further the hard tissues on the face [98]. This gangrenous disease is prevalent in African countries and some parts of Asia and Latin America, often affecting children aged 2–6 years due to malnutrition, dreadful infections, poor hygiene, and feeble immune system [99]. This gangrenous disease is so terrifying that ~ 140,000 cases have been reported annually for 2 decades. The common sufferings of the infected individuals include difficulty while eating and swallowing and facial disfigurement, causing social stigma. If diagnosed at the early stage, specific treatment options include surgical removal, improved nutrition, application of antibiotics, and rehabilitation for treatment [100]. The oro-facial clefts, also called clefts on the lip and palate, are the most common craniofacial congenital disabilities, accounting for a global prevalence of over 1 in 1000 births [101]. As genetic disposition is a major cause, tobacco consumption, poor maternal nutrition, and high obesity during pregnancy influence oro-facial clefts. The surgical interventions along with complete rehabilitation are the possible treatment options.

Several common risk factors include tobacco and alcohol consumption, as well as a high-sugar diet. These factors with unhealthy diet lead to other diseases, such as CVDs, cancer, respiratory disorders, and diabetes [102]. More importantly, diabetes is reciprocally linked to the development of various periodontal diseases and dental caries [103]. The predominant options for maintaining oral health include public health interventions, following a healthy diet with well-balanced sugars rich in fruits and vegetables, reduced alcohol consumption, increased physical activities, and decreased risk of facial injuries. Apart from maintenance, oral health services and regular checks with the dentist play crucial roles. Notably, the unequal distribution of oral health professionals, including general dentists and surgeons, would facilitate access to services that are very low in many countries [104]. As dental equipment is quite sophisticated, oral health care costs are another major barrier for low-income countries. Conclusively, the response of the World Health Organization (WHO) to improved oral health included a “Resolution on Oral Health” in 2021 at the 74th World Health Assembly. The resolution highlighted the preventive method rather than the traditional curative approaches by promoting oral health in schools, families, and work institutions [105]. Further, the World Health Assembly adopted a global health strategy with a vision of universal health coverage by 2030.

Importance of nanoarchitectured components

Prior to exploring the intrinsic features of these nanostructured components and their importance in dentistry, we briefly introduce the history of nanotechnology and its influence on science and, subsequently, in the field of dentistry. Although the advent happened to be in the mid-1950s, nanotechnology is currently being applied extensively in various fields of science and technology. The concept was first explained by Dr. Richard Feynman in 1959 [106]. The notable advancements include the concept of nanotubes in 1991 by Dr. Sumio Lijima [107]. Along this line, extensive research over the past three decades has evidenced the development of various nanostructured materials, including ultra-small sized dots (0D) to multi-dimensional nanocomposites, such as 1D nanotubes to 2D nanosheets and 3D mesoporous silicas [108]. As mentioned earlier, nanomaterials offer highly advantageous physicochemical properties and attractive morphological attributes due to their malleability, high surface-to-volume ratio, and tunable sizes, as well as shapes [109]. In dentistry, the integration of nanotechnology began in the early 2000s, and the term “nano-dentistry” was coined by Dr. Freitas Jr [110]. The research progressed by Dr. Freitas Jr. resulted in the development of nanomaterials and nanorobots towards the regeneration of dentition and the development of dentifrobots, i.e., robots in dentifrices [111]. Although expressed as impossible in the early stages, it is now being researched extensively for the utilization of various nanostructured components in different modes to improve dental health [112]. This section provides an overview of various nano-sized materials for these dental applications, highlighting their importance compared to conventional therapeutic choices. Although there seem to be some similarities with the final nanoarchitectures section, herein, we intend to demonstrate their impact, highlighting the roles of nanoarchitectures and their modifications.

Impact of nanostructures and their surfaces

Prior to exploring the importance of nanostructures in treating various dental ailments, it is quite crucial to understand the impact of designed nanoarchitectures and their modified surfaces on the improvement of therapeutic efficacy. As notified earlier, several efforts have been dedicated to synthesizing various nanostructured components from natural and synthetic sources in dentistry. These innovative biomaterials can treat diverse oral diseases along with their root causes in many ways, such as anti-microbial nanomaterials [113], remineralized nanoconstructs, regenerative composites, and tooth nano-whiteners [114]. Some of these notable nanomaterials with extensive ability for encapsulation of anti-microbial agents can eradicate biofilms [115]. Moreover, the anti-caries materials deposited with bioactive nanocomponents improve remineralization [116]. The encapsulated nanomaterials provide appropriate room and enable the growth of cells during tissue regeneration. Combining all their beneficial aspects, these nanoparticles will offer a new paradigm shift in the dentistry field (Fig. 3, Table 1) [117].

Fig. 3

Illustration presenting the diverse key functionalities of the designed nanoarchitectures for improved dental health, including drug (anti-microbial/anti-inflammatory/anti-cancer) delivery characteristics, hard-tissue remineralization, and regeneration of soft oral tissues

Table 1 Diverse nanostructured components with specific action against various dental-related ailments

Typically, the microenvironment of various native tissues is exceptionally organized with numerous nanofibrous elements, including but not limited to elastin, collagen, and other proteins. On the one end, these complex biomolecules significantly guide cell behavior. On the other hand, these ultra-small components offer a convenient way to alter the biochemical and mechanical cues in the biological microenvironment during the application of various delivery platforms. Notably, it is imperative to understand the importance of various nanoparticles and their interactions with the oral microenvironment towards improved delivery. Considerably, several attributes play crucial roles in the performance efficacy, such as the complex microenvironment and its components, as well as the morphological characteristics of the designed nanoparticles. Regarding the applicability of various nanoconstructs in oro-dental diseases, the interactions and interplay between nanoparticles and membranes of cells/bacteria. Considering these aspects, the designed nanoplatforms with alterable surfaces and immobilized organic linkers may improve the hydrophobicity, enhancing the interactions with the cell membrane and the biomolecules in the oral microenvironment. In this context, 1D (TiO₂ nanotubes) and 2D (nanosheets) architectures play crucial roles in offering better control over the degree of surface functionalization [36, 118, 119]. Contrarily, the reactive plasma treatments could extend the hydrophilic stability and wet storage on TiO₂ nanotube surfaces, resulting in the improved viability and compatibility attributes of cells [120]. Moreover, the surface treatment often affects the physicochemical properties of the designed nanoconstructs, leading to altered biological responses. In one instance, titanium discs were exposed to altered surface treatments and the adhesion of osteoblasts and bacteria [121]. These improved interactions and altered surface topology, including those coated on the dental implants, enhance the delivery efficacy of the therapeutic nanoplatforms, presenting enhanced antibacterial efficacy and osteo-inductive performance [118]. Moreover, the cells may respond to the 3D topology of encapsulated nanoparticles in the biomimetic scaffolds toward tissue regeneration. These attributes, along with tunable physicochemical characteristics, may provide substantial scope toward enhanced performance in the oro-dental applications.

Drug delivery

Several dental-related disorders often begin with the deposition of bacteria, such as gingivitis and dental caries, in the gaps of teeth and gums. In terms of exhibiting anti-microbial characteristics, several conventional anti-microbial solutions, such as mouthwashes and other formulations with various antibiotics, have been applied to ablate the deposited bacteria on the tooth and gums and cure different tooth- and gum-related diseases [122]. Although anti-microbial solutions work to execute the bacterial ablation effect, several traditional formulations suffer from notable disadvantages in terms of formulation and performance aspects. Predominantly, the formulation of various dosage forms often suffers a major limitation of the poor solubility of hydrophobic drugs, limiting their successful formulation [123]. In terms of performance, it is extremely challenging to eradicate formed biofilms, leading to increased anti-bacterial resistance and resulting in deprived therapeutic efficacy [124]. To this end, several advancements have been evidenced in designing various kinds of materials in the nano-sized range, which could ultimately act through multiple mechanisms by addressing the limitations of traditional anti-microbial formulations. Considering the formulation strategies, it is feasible to fabricate various anti-microbial nanoformulations either by encapsulating different antibiotics or generating anti-microbial materials. Owing to the high surface-to-volume ratio, several kinds of antibiotics can be encapsulated in their pores of the porous nanomaterials (for instance, mesoporous silica) [125] or on the surface through conjugation in the non-porous nanomaterials (polymeric constructs or 1D or 2D materials) [118, 126]. Specifically, 1D nanotubes (for instance, TiO₂) with extensive surfaces showcase exceptional topology with favorable antibacterial outcomes [119]. Regarding delivery, these innovative nanomaterials encapsulated with antibiotics substantially improve the solubility of the hydrophobic drugs, leading to their improved performance efficacy [127].

Typically, the nanomaterials encapsulated with antibiotics act through various mechanisms, depending on numerous factors in terms of types of nanoparticles and their delivery patterns. Several mechanisms at multiple levels include electrostatic interactions on the surface, metal ion hemostasis in the cytoplasm intracellularly, and genotoxicity and inhibition of signal transduction in the nucleus [127]. Establishing the electrostatic attractions is the most predominant way that anti-bacterial materials act through crosstalk between the material and the bacterial surface, starting at the cell wall doors. Considering the electrostatic interactions, the delivery efficacy and eventual anti-bacterial action of nanoparticles often depend on the surface charge as the positively-charged nanoparticles usually enable the attachment with the negatively-charged bacterial surface through the electrostatic attractions [128]. The successful interactions and subsequent accumulation at the cell wall doors would facilitate the successful internalization of the bacteria for the delivery of drugs [129]. In addition, the excessive accumulation would damage the cell wall framework, leading to cell membrane disruption and allowing intercellular content leakage and eventual ablation of bacteria [130]. Further, the binding of nanoparticles with mesosomes affects the respiration, division, and eventual replication processes, resulting in reduced bacterial infection. The metal ion homeostasis plays a crucial role in the anti-bacterial action of various metallic nanoparticles; the classic example is the silver nanoparticles (AgNPs) [131]. Typically, different intracellular metal ions often participate in various metabolic activities in microbes. The excess deposition of metallic nanoparticles intracellularly and further irreversible damage to the cell wall would disturb the intracellular metal ion hemostasis and metabolic functions [132]. In this context, AgNPs-coated titanium interfaces have been applied to treat the undesirable bacterial infection [133]. Moreover, the nanomaterials are capable of generating reactive oxygen species (ROS) and attacking cell membranes, causing disturbing respiration and decreased energy production. Some metal oxide-based nanoparticles result in the formation of ROS by actively participating in the redox cycling [134]. In addition, several protein-denaturing nanomaterials often act by the formation of carbonyls, catalyzing the oxidative process of the amino acid chain and leading to the protein denaturation [135]. In addition to surface and cytoplasm, the anti-bacterial nanomaterials act in the cellular core, i.e., the nucleus [136]. Owing to their electrical properties, the internalized nanoparticles could interact with the nucleic acid molecules, resulting in an undesirable influence on the chromosomal replication towards inhibiting signal transduction. In addition, these nanoparticles intracellularly act through modulation of cell signaling by altering the phosphotyrosine profiling [137].

Hard tissue biomineralization

Oftentimes, the condition of dental caries affects the quality of teeth, damaging the enamel and teeth subsequently due to bacterial growth. The damaged teeth portions can be fulfilled by remineralizing the hard tissues using various adhesives or resins [138]. These adhesives or resins added with multiple biologically active nanomaterials act as remineralized anti-caries nanomaterials [74]. On the one hand, these nanomaterials remineralize the exposed collagen, preventing its degradation and improving bonding durability [139]. On the other hand, the encapsulated nanoparticles can facilitate the release of highly required calcium and phosphate ions to improve strength at low pH values, promoting the remineralization of the tooth [140]. Moreover, the strong anti-caries action would be facilitated by encapsulating some anti-microbial materials. Remineralization of hard tissues towards treating dental caries follows sequential steps of irrigation, intracanal medicament, and obturation (filling and sealing). The irrigation of the root canal, an initial physical cleaning process, involves the removal of damaged tissues and the introduction of chemicals for preparing the bulk filling process, including the explicit cleaning with anti-microbial agents, demineralization, tissue dissolution, bleaching, deodorizing, and hemorrhage control [141]. Several predominantly applied irrigants include sodium hypochlorite, ethylenediaminetetraacetic acid (EDTA) [15], and chlorhexidine (CHX) [16]. However, some of these irrigants pose compatibility-associated risks. For instance, sodium hypochlorite suffers from a major challenge of cytotoxicity due to the accidental extrusion beyond the apical foramen of the tooth [142]. Considering the limitations of traditional chemicals-based irrigants, several nanoformulations have been developed, possessing enhanced anti-biofilm efficacy and disabling bacterial endotoxins, such as chitosan nanoconstructs [143]. Comparatively, these nanoformulations would be safer in terms of compatibility compared to the sensible release of deadly ROS. Prior to filling the irrigated canal, the root canal is cleaned with the medication referred to as the interappointment intracanal medicaments, employing anti-inflammatory and anti-microbial agents [144]. A typical intracanal medicament applied is the calcium hydroxide paste, which acts as not only an anti-microbial but also a calcium supplement by initiating hydroxyl ions that increase pH and damage microbial DNA, cell membranes, and enzymes [145]. In some instances, other anti-microbial agents, such as AgNPs and chlorhexidine, are mixed with calcium hydroxide, showing enhanced anti-microbial action [146].

The final step of remineralization is referred to as obturation, which is the combination of filling and sealing after the intracanal medication of a canal [147]. Typically, the general bulk fillers, either in the form of solids or semi-solids, along with the sealers, are used to complete the obturation process [148]. The commonly used bulk fillers include silver points, Gutta-percha (GP), and Resilon [149]. The ideal properties of these bulk fillers include compatible, inert, and structurally stable. In recent times, several nanoparticles encapsulated with antibiotics, such as bioactive glass, have been incorporated into these fillers to provide additional benefits, including enhanced mechanical strength and anti-microbial properties [150]. Eventually, the sealing of the filled inert material with the endodontic substances is a crucial step in closing the root canal system, as some of the fillers with flow ability may lead to poor obturation [151]. Sealer is important in overcoming the appropriate deposition of filler and establishing an association with the root dentin. Accordingly, the sealer fills the gaps between the filler and root dentine, achieving the fluid-snug seal [152]. In several instances, anti-bacterial nanomaterials, such as chitosan and ZnO nanoparticles, are added to obturating sealers, facilitating an enhanced anti-microbial action for a long time and mechanical properties, leading to improved remineralization [17, 18].

Regeneration of oral tissues

Indeed, some dental-related ailments often result in the loss of tissues to a great extent, specifically during tooth loss and surgical removal. Indeed, the highly complex extracellular matrix (ECM) microenvironment of native tissues is well organized, guiding cell behavior. However, the regeneration ability of these removed or damaged tissues is quite poor [153]. In this vein, various biomimetic scaffolds for engineering tissues include self-assembled polymers and proteins for cell or drug delivery, as well as layer-by-layer supramolecular complexes. Nevertheless, the reconstruction of damaged tissues using these biomimetic conventional scaffolds may pose various limitations in terms of lack of regeneration abilities. Moreover, the surface coalition with the cells also leads to poor regeneration outcomes due to poor spatiotemporal attributes of the conventional macro-sized materials.

The integration of nanotechnology and encapsulation of several nanoconstructs in the biomimetic scaffolds have offered enormous potential for the functional improvement and structural restoration of tissues [154, 155]. Thus, the integrated nanoconstructs facilitate the host–guest cross-talks and improve regeneration ability [156]. From the host's point of view, the oral tissues could take control of the 3D topology of the designed innovative nanocomposites, improving intercellular communication [157]. From the guest species point of view, the inherent molecular properties of the encapsulated nanomaterials in the biomimetic scaffolds enable the alteration of the spatial rearrangement of their extracellular cues in the ECM. Moreover, these composites enable the improved crosstalk intercellular, enabling the regulation of mechanical signals in the ECM [158, 159]. In addition, the sufficiently high surface-to-volume ratio, abundant surface area, and active surface facilitate the encapsulation of various oro-protective drugs, including antibiotics [160]. Several examples include polymeric nanoconstructs (polylactic-co-glycolic acid, PLGA, polylactic acid, PLA) and inorganic structures (titanium dioxide, TiO₂, calcium fluoride, CaF, Ag, Au, iron oxide nanoparticles, IONPs, and mesoporous silica nanoparticles, MSNs) and their composites [24]. Notably, the particle characteristics (hydrophobicity, curvature, and radius), morphological attributes (size and shape), charge, and coated materials often command the eventual outcome. To a considerable extent, several modifications have been applied, such as immobilizing organic assemblies on the inorganic structures to establish interactions with the biological environment for improved performance [161].

In addition to typical tissue growth using various supplements altering the ECM environment in the oral cavity, stem cells have been employed for tissue regeneration applications. Along this line, human dental pulp stem cells (hDPSCs) can be employed for tissue restoration, in which these specific stem cells can be isolated from the dental pulp of permanent teeth or extracted wisdom teeth. Moreover, periodontal ligament stem cells (PDLSCs) can be harvested from this wisdom tooth to explore the guided periodontal tissue regeneration [154]. Although various sources of stem cells have been available for tissue establishment, in some instances, it is required to improve the odontogenic potential by enhancing their differentiation ability. In this context, some nanoconstructs with exceptional regeneration ability offer improved differentiation efficacy of hDPSc to odontoblastic-like cells, such as inorganic (calcium-based materials, ACP, silicon) and organic (dendrimers) [162,163,164]. These hDPSCs can be encapsulated in the scaffolds with the mineralized ECM-like components for their improvement of regeneration efficacy, inducing intrafibrillar mineralization of single-layer collagen fibrils [163]. In addition to regeneration potential expressing specific odontogenic/chondrogenic-related genes, these nanoparticles functionalized with peptides may result in the enhanced mineralization process and nerve regeneration of pulp to the neuronal differentiation potential of hDPSCs [162, 164].

Synthetic approaches

Over the decades of research, several approaches have been developed for the synthesis of various kinds of nanomaterials, depending on the physicochemical properties, solubility of the precursors, dimension, size, and applicability of the end products [165]. Despite various kinds of strategies, most of these synthesis methods have been broadly classified into two predominant strategies, i.e., top-down and bottom-up approaches [166]. The top-down process refers to reducing the size of initial bulk materials to nano-sized constructs using externally controlled conditions, for instance, ball milling strategy [167]. The bottom-up approach reduces or miniaturizes the materials to the atomic level and subsequently assembles them into nanometer-sized constructs in an organized manner [168]. For instance, the self-assembly approach results in the colloidal dispersions. Comparatively, the bottom-up strategies are highly advantageous and applied more over the top-down methods due to various reasons, such as the formation of homogenous composition, ease of controlling ability by altering the synthesis conditions, better ordering of molecules, and formation of uniformly dispersed materials [169]. Notably, the selection of an appropriate method often depends on the requirements based on form, dimension, eventual particle size, and yield of the product. Several methods (physical- and chemical-based) have been applied for synthesizing various nanomaterials, such as hydrothermal/solvothermal, magnetron sputtering, ball milling, chemical vapor deposition, solid-state reaction, photoreduction, sol–gel, and spray pyrolysis techniques [170]. Although these methods have been employed extensively, they have limitations in terms of high-temperature requirements, time consumption, and energy prerequisites, requiring the appropriate selection and optimization of the conditions. In this article, we selected some commonly employed techniques, such as self-assembly, templating, phase separation, sonochemical, and miscellaneous (electrospinning, exfoliation, ball milling, and microwave-assisted irradiation) approaches (Fig. 4).

Fig. 4

Schematic illustrating various predominantly applied synthesis approaches (top-down and bottom-up) for generating multiple nanoconstructs in diverse dimensions (0–3D) of miscellaneous precursors

Self-assembly

Self-assembly has emerged as one of the important processes in synthesizing materials, in which the precursors or components are either arranged spontaneously or linked to each other, systematically forming the ordered aggregates without the influence of any external stimuli [171]. This intrinsic process is predominantly evident, including the building blocks in the human body, in which various components can be rearranged, ranging from small-sized (nanometric domains) molecules to large-sized (macroscopic) components that are visible to the naked eye. This process can be broadly classified into atomic [172], molecular [173], and colloidal self-assembly dispersions. The critical features of self-assembly include the appropriate favorable conditions and appropriate charge for establishing the interactions between the pre-existing components. Accordingly, this arrangement of molecules into supramolecular architectures often manifests through diverse mechanisms involving direct and indirect interactions in the solvent environment, such as inter-/intra-molecular forces and Hamaker interaction forces. The arrangement is favorable by minimizing Gibb's free energy, enhancing the attraction between them. These molecules with extended chemical bonds, along with weak interactions, could encompass the nanoscale building blocks at all length scales and dimensions ranging from 0 to 3D nanomaterials [174]. Other advantages include flexibility and ease of scalability [175]. However, the major challenge of self-assembly is that it is difficult to control the designed architectures at appropriate desirable sizes and challenging to predict the outcome.

Phase separation

The phase separation process is the chemical segregation of a single homogeneous mixture into different forms while reducing the free energy. Phase separation-based techniques are classified based on phases, including liquid-phase- and gas-phase-based separations [176]. Among them, the liquid phase requires more attention as it involves an additional phase, resulting in agglomerated particles. This liquid-based approach involves the precipitation of nanoparticles in desired particle size and altered morphological distribution through diffusion or the Ostwald ripening methods [177]. However, it should be noted that the desired morphological attributes could be evident through the strict optimization of the substrate concentration and other conditions, such as the temperature of the reaction. Often, this process results in the extensive aggregation of the components, resulting in the aggregated products over micron-sized structures, limiting their applicability. To overcome this limitation, some additives can be applied while fabricating nanometric domains, such as surfactants [178] or electrolytes [179]. However, these may form contaminated interfaces. The formation of nanometric domains in the separation approach involves a series of steps, including the initial formation of the nucleus through a chemical reaction, subsequent aggregation of molecules, and coalescence to nanostructures. The application of high temperatures may result in large-sized highly stable agglomerates, which can be separated and pulverized into uniform-sized small particles.

Template-based synthesis

The template-based synthesis approach is applied to fabricate various nanometric domains using the sacrificial templates [180]. including soft (amphiphilic surfactants and vesicles) [181] and hard templates (copper oxide) [182]. This approach is often used to fabricate porous and non-porous constructs, in which these sacrificial templates can be removed to form mesoporous to large-sized porous and hollow architectures. For instance, CTAB is used to generate MSNs [183] and copper oxide for hollow architectures. Initially, the templates are arranged in the required ways considering their physicochemical features, which are further utilized to deposit the precursor of the material of interest. Additionally, the sacrificial templates are removed, resulting in the desired porous architectures. These porous arrays can be employed to encapsulate the desired guest species. Several particle designing strategies include chemical vapor deposition [184], chemical polymerization [185], electrochemical deposition, and sol–gel approaches. This templating approach can be applied to synthesize various nano-sized domains of diverse materials, metals, semiconductors, and other solids in various dimensions, such as 1D (tubes/belts/rods) to 3D materials (hollow spheres) [186].

Sonochemical approach

The sonchemical process has garnered enormous interest from researchers in generating nanoparticles with desired morphological attributes [187]. This facile approach addresses a major limitation of energy requirement compared to other conventional techniques. The synthesis involves the application of ultrasound radiation at a frequency range of 20 kHz to 100 MHz and temperature for acoustic cavitation, in which the sound waves act as an energy source for the conversion of reactants to products [188]. The sound wave strikes the precursors and results in the formation of bubbles. After breaking the bubbles due to acoustic cavitation, the microenvironment surrounding the bubbles leads to high tension, raising the local temperature and forming a high-pressure region [189]. The sudden change in the temperature and pressure conditions activate precursors, forming nanomaterials due to the kinetic energy gained during the reaction kinetics [190]. This facile one-step approach with no additional heat treatment for crystallinity results in high surface area with limited agglomeration as the heat treatment increases crystallinity and reduces surface area [191]. Various inorganic nanoconstructs of ultrasmall-sized constructs, along with convenient fabrication of metal-doped composites and alloys, result in desired particle size distribution for various applications, including biomedicine [192].

Miscellaneous

In addition to various major synthetic strategies with defined principles of nanometric domain synthesis, several other methods have been discussed hereunder, highlighting their importance and shortcomings in synthesizing multiple kinds of nanoparticles. These specific approaches include ball milling, microwave-assisted irradiation, electrospinning, and exfoliation.

Ball milling is one of the most applied top-down processes, referred to as a mechanical operation often applied not only in the food industry for grinding powders but also for synthesizing various nanocomposite materials from their bulk counterparts [193]. This eco-friendly physical modification approach (no solvents required) offers different mechanical actions based on the balls made of stainless steel, ceramic, or rubber, increasing the mechanical reactivity and spatial distribution of precursor components. The formation is based on the principle of applying friction, shear, collision, and impingement of various forces, resulting in the microscopic structures of the bulk components [194]. These balls inside the grinding jar result in frictional forces due to their movement, in which the resulting kinetic energy sufficiently breaks the bonds between the components [195]. The substantial mass and energy transfer leads to the breakdown of the structure. These reduced sizes alter their morphology and functional properties, including dispersibility, heat stability, and retrodegradation. Several operating parameters include the speed of the rotating balls, ball-to-powder ratio, and grinding time, among others. This approach offers advantageous features, such as ensuring higher safety, being facile in nature, cost-effectiveness, and the absence of undesirable by-products. Nevertheless, this approach may result in the aggregation of non-homogenous products, hampering their applicability.

Exfoliation is one of the top-down approaches often used to synthesize single-layered sheets from the bulk sheets of their counterparts. Typically, the bulk sheets, which are composed of a stack of monolayer sheets, are exfoliated into single sheets [196]. This process results in the nanosheets exhibiting improved physicochemical, magnetic, electric, and optical properties [197]. The method of exfoliation can be performed using various strategies based on swelling and delamination, including liquid-phase exfoliation (urea and formamide), plasma-based separation, and dry delamination. More often, the exfoliation approach may result in defect structures, which could present improved physicochemical features. Although convenient and facile, this approach requires large amounts of chemicals and solvents, hampering their applicability. Moreover, the separation of single sheets is highly challenging to get in high yield.

Electrospinning is one of the traditional and widely applied techniques for developing fibrous architectures, such as nanofibers, which can be patterned using the co-axial spinnerets influencing the functional attributes [198]. The predominant advantages of electrospinning to counter the contemporary synthesis methods include one-step, facile in nature, safe, and cost-effective [199]. Moreover, this approach can be effectively applied to design desired nanoarchitectures by substantially optimizing various operating parameters, such as voltage, feeding rate, and tip-to-collector distance. The morphological features can be modified by altering these operational parameters. The major challenge is to generate ultrasmall-sized nanoarchitectures in defined forms except fibrous architectures. Microwave-assisted irradiation is the most applied technique in various chemical reactions due to the advantages of short reaction time (minutes instead of hours), non-utilization of solvents, and high yields [200]. This approach reduces the utilization of organic solvents in large amounts and saves energy consumption and cost. Considering these attributes, this approach has been applied recently for the synthesis of nanomaterials (for instance, graphene) due to the rapid reaction rates and homogenous heating of the precursor materials in the reaction system [201].

Nanotherapeutic solutions

As one of the exquisite innovations of humankind, nanotechnology has attracted enormous attention from researchers since its advent in the mid-1950s towards various innovative applications, including medicine [24]. However, these innovative nano-sized constructs have been applied recently as therapeutic solutions to treat and prevent various dental-related infections. In this framework, several advancements have been evidenced by the generation of diverse kinds of nanoparticles based on the source of precursors, including natural (plant-, animal, and marine-life) and synthetic (organic-, inorganic-, as well as organic–inorganic) nanocomposites. More often, these innovative ultrasmall-sized nanomaterials can be incorporated into various macro-sized constructs for improved applicability, such as resins, ceramics, and metals, among others. These composite mixtures can be applied to various locations of the teeth based on the relevance and type of ailment, such as prosthetics, endodontics, periodontal treatments, and comprehensive implantation. Moreover, the therapeutic effects, either by themselves or through encapsulating various drugs, can address various dental ailments, such as anti-inflammatory agents for addressing gingivitis for gum-related disorders, anti-microbial agents for treating periodontal and cariogenic bacteria and remineralizing nanocomposites, for curing dental-related diseases by reducing the hypersensitivity of the tooth. In this section, we discuss various kinds of nanoconstructs from natural (plant-, animal-, and marine-derived) and synthetic (organic/inorganic/organic–inorganic) sources, highlighting the oral applications towards improved dental health (Fig. 5, Table 2).

Fig. 5

A representation illustrating various predominantly applied nanoarchitectures based on natural (plant/animal/marine-derived) and synthetic (organic-/inorganic-/organic–inorganic-based) nanoconstructs of miscellaneous precursors

Table 2 A summary of various nanostructured components for various dental-related ailments

Nature-derived constructs

Indeed, nature has provided us with enormous opportunities in terms of therapeutic potential through various ways, such as drugs and sources for synthesizing materials. Although these therapeutic materials are synthesized in a facile way with mild synthesis conditions and ultra-facile precursors, the materials have emerged as highly complex architectures through evolution for millions of years. Considerably, these complex architectures offer exceptional mechanical properties, outperforming the synthetic components and their combined mixtures. In addition, these natural components exhibit large diversity with extensive sources of precursors with degradability attributes. In this regard, various small molecules from natural sources have been widely applied as anti-microbial agents and remineralization of enamel [202]. Several sources, such as plants, animals, and marine life, have been available for the fabrication of various nanocomposites. Although, in some instances, various nature-derived extracts are not in nanometric domains, it is worth discussing their efficacy in addressing oral ailments. In this section, we present a detailed view of various nature-derived components, highlighting their advantages and applicability against various oral diseases.

Plant-derived extracts

The extracts of various plants with exceptional medicinal value have been employed for the treatment of different ailments, including oral diseases. Predominantly, these phytochemicals possess various bioactive components, including but not limited to flavonoids, phenolic acids, terpenoids, tannins, and alkaloids, among others. These medicinal components with improved pharmacological (anti-bacterial, anti-oxidant, anti-cancer, and anti-inflammatory) activities are of particular interest in various oral conditions of periodontitis, gingivitis, and other oral-related ailments [203]. Typically, these phytochemicals with aromatic features and anti-bacterial effects have been applied in traditional medicine as mouthwashes to act against various biofilms effectively. Along this line, several examples include Salvia sclarea L., clary, Melaleuca alternifolia, Punica granatum L. fruits, Matricaria chamomilla L., Rosmarinus officinalis, Punica granatum L. Lippia sidoides Cham., Scutellaria baicalensis, and Camellia sinensis, among others [203,204,205,206]. Notably, various biofilms are designed by the microbes as an ecological strategy for establishing multiple communities of various bacterial species. Furthermore, the formed biofilm is developed into a reservoir of chronic infections, resulting in the acquired resistance to the host immune system and anti-bacterial molecules. Importantly, caries and periodontitis are caused by several biofilms, resulting in the challenges of treating oral diseases. Considering the anti-bacterial resistance, the utilization of medicinal plants seems to be an affordable option for manipulating the acquired resistance by various bacterial communities in the biofilms. Moreover, these natural phytochemicals are better than chemotherapeutics in terms of no adverse effects. In an instance, Casarin and colleagues demonstrated the fabrication of Melaleuca alternifolia-based nanoparticles with 0.12% chlorhexidine gluconate against oral microorganisms in participants [204]. The designed nanoparticles were subjected to explore the anti-biofilm and anti-inflammatory effects on biofilm-free (BF) and biofilm-covered (BC) surfaces for comparison by assessing the Quigley & Hein plaque index (QHPI), gingival crevicular fluid (GCF) volume of the patients. Interestingly, the nanometric domains with significantly lower mean QHPI on BF and BC surfaces presented exceptional anti-inflammatory effects with better control over the biofilm. Although various plant extracts have been employed against oral infections, it is yet to explore the establishment of various nanotechnological solutions comprehensively using these exceptional medicinal plants. In addition, further clinical trials with different testing methods are required to explore their clinical applicability.

Considering the fabrication of nanoparticles, various physicochemical strategies have been developed over the past few decades, including chemical vapor deposition, lithography, laser ablation, electro-deposition, and sol–gel techniques [36]. However, these approaches suffer from various limitations, such as expensive and deprived biocompatibility and reproducibility challenges. Moreover, several methods are environmentally unfriendly due to the utilization of organic solvents, hampering their utility. In search of cheaper and eco-friendly sources, several reports demonstrated the utilization of nature-derived extracts from plants and microorganisms, which are subsequently applied for the fabrication of metallic nanoparticles. Among various sources, plant-based extracts (root, bark, leaf, and flowers) can be rapidly prepared for the synthesis of metallic nanoparticles in vitro using a single step, requiring no sophisticated purification methods [205]. These extracts containing various phytochemicals (e.g., terpenoids, alkaloids, and phenolic substituents) and secondary metabolites (amino acids, vitamins, proteins, polysaccharides, enzymes, and antioxidants) reduce to corresponding metallic nanoparticles. The classic example of plant-based reduction is the synthesis of AgNPs, which are synthesized by optimizing various formulations (pH, precursor concentration, and phytochemical composition) and processing parameters (reaction temperature). The conditions of basic pH and optimal temperature are often favorable for the synthesis of these spherical-shaped AgNPs. More often, these plant extracts act by enhancing the reduction efficacy of the metal precursors. Nevertheless, the synthesis of spherical-shaped AgNPs is usually favorable at high temperatures around 100 ºC. To this end, the alternative route of AgNP synthesis using the mesophilic organisms utilizes ≤ 40 ºC, resulting in smaller-sized AgNPs. Together, these plant-derived AgNPs can be fabricated at ambient temperatures ranging from 25 ºC to 37 ºC. These metallic nanoparticles can be highly effective for dental-related ailments, predominantly for the anti-microbial effects, attributing to several synthetic parameters, including but not limited to surface composition, charge, and size [207]. These green approach-based metallic nanoparticles with intrinsic features of stability and compatibility attributes could be substituted with chemically synthesized metallic nanoparticles due to various reasons, such as cost-effective and high performance efficacy against oral pathogens [208, 209]. Several plant sources include Azadirachta indica (A. indica), Ficus bengalensis (F. bengalensis), and Salvadora persica (S. persica), which have been applied for the synthesis of AgNPs for dental-related ailments [203, 205]. Moreover, these biogenic nanoparticles eventually showed improved anti-microbial effects compared to chemically synthesized nanoparticles and traditional antibiotics. In addition, several antibiotics in combination with AgNPs from the leaf extract were highly effective against various microorganisms associated with dental caries and periodontal diseases, ablating Escherichia coli (E. coli), Streptococcus mutans (S. mutans), Lactobacillus lactis (L. lactis), Lactobacillus acidophilus (L. acidophilus), Staphylococcus aureus (S. aureus), Bacillus subtilis (B. subtilis), Pseudomonas aeruginosa (P. aeruginosa), Micrococcus luteus (M. Luteus), and Candida albicans (C. albicans) [205]. Owing to these aspects, these biogenic metallic nanoparticles can be added with different formulations, such as mouthwashes and toothpaste, offering anti-bacterial activity towards sustainable therapeutic effects against oral pathogens.

Animal-derived composites

The plentiful endowment of animal tissues offers a potential solution to address the desperate shortage of human tissues substantially. Considering the material affordability, several animal tissues can be grown into functional organs due to their structural and functional attributes. In the field of tissue engineering, repairing abnormal or damaged tissue remains a significant challenge for external scaffolds due to the lack of stimulation of the tissue microenvironment and supportive components for tissue growth. In this vein, decellularized ECM (dECM), an exquisite biomaterial from natural tissues, has garnered enormous attention from researchers due to their biocompatibility and malleability attributes, for instance, dECM based on porcine tissues. These advantages, along with various exceptional structural and morphological characteristics, facilitate natural cell infiltration, improving tissue regeneration. In addition, dECM possesses various proteins (collagen, proteoglycans, fibronectin, and glycoproteins) and exceptional growth factors simulating the tissue environment. These natural tissue-mimicking environments enable the transmission of appropriate signaling cues and facilitate the proliferation and differentiation of the deposited cells in the dECM matrices. Along this line, some efforts have been made to employ dECM-based scaffolds for improved oral health. Typically, the poor orientation of fibers and mismatched bone-ligament interface fusion may result in periodontal defects. In a case, Yang and coworkers addressed these defects by designing a 3D bioprinted periodontal module using the gelatin/dECM composite bioink (Fig. 6A) [210]. Considering the exceptional mechanical properties and biochemically conducive environment, these biomimetic scaffolds offered high-precision topographical cues, regulating encapsulated cell behavior. In addition, several important attributes included enhanced immunomodulatory effects, reduced proinflammatory factors released by M1 macrophages, and decreased local inflammation. Moreover, these scaffolds presented well-aligned periodontal fibers, the anchored structures of the bone–ligament interface, and highly mineralized alveolar bone, improving the periodontium regeneration potential of hybrid periodontal tissues in Sprague–Dawley (SD) rats. Considering the exceptional attributes, dECM from the other sources can be applied towards the development of personalized periodontium regeneration. Although it opens a new avenue for improving oral health, there is a long way to go as it requires numerous trials at different levels of animal and human for their applicability in clinics.

Fig. 6

Reproduced with permission from Ref. [210] Copyright 2023, John Wiley & Sons. B The preparation procedures for WSM extraction using the UAE strategy. FESEM images of an enamel-like HA layer grown on acid-etched enamel. C The remineralized enamel at different additions of WSM: (i) without addition, (ii) 0.025 wt%, and (iii) 0.075 wt%, respectively. (Yellow arrows show the re-mineralized layers). Reproduced with permission from Ref. [211] Copyright 2022, Elsevier. D Schematic illustrating the outline of various natural polyphenols (proanthocyanidins (PA), myricetin, resveratrol, and kaempferol) from plants on resin-dentin bonding performance towards remineralization. Reproduced with permission from Ref. [202] Copyright 2023, Dovepress

A Schematic overview of the 3D bioprinting of periodontal modules with GelMA/dECM bioink encapsulating human DFCs for periodontal regeneration.

Marine-derived components

Marine life has provided us with enormous opportunities for dental health, such as seashells, bones, and corals, among others. These marine components offer exceptional biocompatibility and mechanical properties, which are of particular interest towards displaying various functional attributes of osteoconductive and osteogenic properties, as well as anti-thrombogenic and anti-microbial activities. Enamel, the outermost layer of hard tissue, is the hierarchical structure, which is an outermost surface that might be prone to damage during external stress or bacterial infection in caries. The controlled spatiotemporal order of this organic matrix is referred to as amelogenin, and the regulation of the ameloblasts plays a crucial role in the mineralization of hydroxyapatite. Nonetheless, the enamel loses its ability to regenerate due to the apoptosis of the ameloblasts and eventual degradation of amelogenin. In an attempt to reconstruct the enamel-like hydroxyapatite structures, Xing et al. isolated abalone nacre water-soluble organic matrix (average size of ~ 155 nm) using the ultrasonication-assisted extraction without disturbing the bioefficacy towards hard tissue mineralization (Fig. 6B, C) [211]. These components, inspired by the mineralization of mollusk nacre by nature, substantially improved the yields of the protein (7.60–9.60%) and polysaccharide (2.59–3.34%). These innovative structures coupled significantly induce the growth of enamel-like crystals to facilitate the biomimetic remineralization of the enamel towards forming a smooth tooth surface of a mineralized layer in vitro, enabling the elastic modulus and restoring the tooth permanently. In another instance, the propolis nanoparticles and curcumin from a plant source were applied to bovine tooth remineralization based on photodynamic therapy (PDT) [212]. For example, various natural polyphenols (proanthocyanidins (PA), myricetin, resveratrol, and kaempferol) from plants also showed improved resin-dentin bonding performance by inhibiting the matrix metalloproteinase (MMP) activity (Fig. 6D) [202]. In another instance, Yan and coworkers designed potential dental materials by comprehensively analyzing various natural mollusk shells (Strombus gigas, Strombus latissimus, Lotoria lotoria, Cypraecassis rufa, Lambis lambis, Chicoreus torrefactus, Hippopus porcellanus, and Tridacna squamosa). Interestingly, the authors systematically demonstrated their feasibility by determining their aesthetic performance, mechanical and biomedical properties, as well as machinability. Among various species, the Strombus latissimus shell offered exceptional flexural strength and high fracture toughness, exhibiting highly stable crack extension over the commercially available 3Y-TZP dental materials. Considering the biocompatibility and antifungal attributes due to hydrophilicity and negative surface charge, these specified natural mollusk shells could offer a unique combination of natural teeth-like characteristics towards oro-dental applications. Although the in vitro findings demonstrated exceptional therapeutic abilities, it is further required to demonstrate their in vivo capabilities.

Organic (synthetic) constructs

Several organic-based nanoparticles have been synthesized for various biomedical applications, including the treatment of dental-related ailments. In this framework, different kinds of polymeric constructs with a carbon backbone include polymeric (PLGA, PLA, chitosan, and alginate), liposomal (DSPE and cholesterol), micellar/vesicular (surfactants), collagozomes, and dendrimer-based constructs. The arrangement of these polymers into nano-sized particles is often facilitated by their assembly based on various intermolecular interactions based on coordination, ionic, hydrophobic, and Van der Walls forces. Like inorganic species, these polymeric delivery systems can encapsulate different drugs (anti-inflammatory, anti-microbial, and anti-cancer drugs) and deliver them appropriately. In contrast to inorganic species, these organic species are preferred due to their facile synthesis, colloidal stability, biocompatibility, and degradability. In addition, these organic species with supramolecular structures could overcome the macrophage escape and are safer to use for biomedical applications compared to inorganic species. However, these constructs suffer from poor thermal stability and bioavailability issues, resulting in poor dosage-related risks. Accordingly, there exists a debate between the organic and inorganic-based materials regarding their properties and performance attributes.

Polymeric conjugates

Recently, several efforts have been dedicated to the application of various polymeric nanoparticles for the treatment of dental ailments. In this vein, different kinds of polymers employed for the fabrication of nanoplatforms for the delivery of antimicrobials and scaffolds for engineering tissues include PLGA, polyethylene glycol (PEG), PLA, chitosan, and alginate, among others. The predominant role of different polymeric constructs has been the protection of teeth and gums from bacterial infections. Although several delivery platforms for the release of antibiotics have been developed for teeth protection, the resultant high-protein biofilm formed for their defense is highly challenging in cracking down bacterial infection on the surface of teeth. In addition, these consequences substantially result in the development of resistance to antibiotics, limiting their bioavailability and reducing efficacy. To address the adequate penetration, targeting ability, and degradation of biofilms, several intelligent nano-delivery systems have been developed to improve biofilm permeability and increase their bioavailability. In an attempt to overcome the dreadful hypoxic biofilm, low pH, and nutritional deprivation microenvironment, Wang and colleagues demonstrated the Boron dipyrrolidyl iodide (BODIPY-I)-based phototherapy to eliminate pathogenic bacteria under laser irradiation (Figs. 7A, B) [213]. By decorating these nanophotosensitizers with guanidine and galactose and copolymerized perfluoropolyether through self-assembly, these formulations offered the oxygen self-sufficient capability, greatly limiting the oxygen-dependent PDT effects. In addition, the positively charged surfaces of the formulation enhanced biofilm permeability towards eradicating oral biofilms. These nanophotosensitizers with positively charged surfaces inhibited the recolonization of S. mutans with improved efficacy against dental biofilms, preventing secondary infections without harming the surrounding healthy tissue in the oral cavity. In addition to being antimicrobial, these polymeric conjugates can be employed for the ablation of oral carcinomas, specifically oral squamous cell carcinoma (OSCC). In a case, Zeng and colleagues fabricated the targeted drug delivery platform based on folic acid (FA)-modified PEG-PLA nanoparticles encapsulated with JQ1 [a small-molecule inhibitor of bromodomain-containing protein 4 (BRD4)] (Fig. 7C) [214]. These targeted nanoparticles could not only improve the formulation targeting tumor tissues but also prolong the half-life of the encapsulated drug. The internalized nanoparticles successfully inhibited carcinoma growth, inducing tumor apoptosis and preventing tumor angiogenesis, as well as the polarization of M2-type macrophages.

Fig. 7

Reproduced with permission from Ref [213]. Copyright 2023, John Wiley & Sons. C Schematic representation of the formation of FA-PEG-PLA-JQ1. Reproduced with permission from Ref [214]. Copyright 2024, Elsevier. D (i) Schematic diagram of the construction of a drug sustainable release system and its application in bone regeneration. Physical characteristics of hollow polydopamine (HPDA) nanoparticles. (ii) TEM image of ZIF-8. (iii) TEM image of HPDA nanoparticles. Reproduced with permission from Ref. [215] Copyright 2021, Nature Publishing Group

A The principle of nanophotosensitizer, p(GF/GEF)-I, to eradicate caries-causing biofilm. A Schematic illustration of the construction of p(GF/GEF)-I. B Mechanism of effective removal of biofilm by p(GF/GEF)-I nanoparticle-mediated photodynamic therapy. The p(GF/GEF)-I species penetrate the biofilm, subsequently bind to pathogenic bacteria in the biofilm, and induce the quick generation of a high level of ROS that can damage cell membranes and kill bacteria. Self-oxygenated nanophotosensitizer improves PDT efficiency and ultimately significantly disperses biofilms.

In addition to drug delivery, several organic constructs have been applied as nano-delivery systems for bone regeneration [215] and vascularized pulp regeneration [216]. In a case, hollow polydopamine nanoparticles were developed based on the templating approach of ZIF-8 MOFs, which could efficiently encapsulate and deliver four types of osteogenic drugs (Fig. 7D) [215]. Moreover, these polydopamine nanoparticles with high biocompatibility could effectively promote the proliferation of rat bone marrow mesenchymal stem cells (rBMSCs) and their osteogenic differentiation in vitro. In another case, Ilhan and colleagues demonstrated the encapsulation of clindamycin phosphate and BMP-7 growth factor in the polymeric nanoparticles for alveolar bone regeneration [217]. Yuan and coworkers demonstrated the regeneration of vascularized pulp using the GelMA cryogel microspheres loaded with PLGA nanoparticles and stem cells from human exfoliated teeth [216]. The designed nano-in-micro constructs with controlled release ability showed exceptional promotion of vascularized tissue regeneration by subcutaneous implantation in mice. These biocompatible and biodegradable organic constructs possessed exceptional sustained release and differentiation abilities to treat bone defects in clinical practice and endodontic regenerative dentistry. Although these organic constructs offer precise compatibility and degradability attributes, several features of stability issues, and precise and sustained release of therapeutic cargo are required to be addressed for the treatment of dental ailments.

Although traditional polymers in solid forms have become exquisite alternatives to drug delivery and tissue regeneration, several drawbacks still may limit their applicability, such as poor stability, strong hydrophobicity, and adverse effects due to deprived colloidal stability. To this end, polymer-based hydrogels have been employed for localized drug delivery due to their exceptional hydrophilicity, tailorable shapes, mechanical characteristics, and malleability, which are of particular interest for oral-based ailments. Along this line, several exceptionally intelligent hydrogels with stimuli-responsive features have garnered enormous interest from researchers in delivering drugs (anti-microbial and anti-inflammatory agents). These smart hydrogel-based constructs encapsulated with drugs offer promising advantages, such as on-demand release, long action time, and low administration frequency, resulting in their improved bioavailability. Specifically, smart hydrogels can be designed with pH and enzyme-responsive stimuli. In terms of pH-responsiveness, biofilms contain low pH in the bacteria-rich environment, facilitating improved delivery in the affected area. In addition, several oral pathological conditions, such as dental plaques and periodontal diseases, express MMPs, specifically MMP-2, involved in connective tissue degradation. Thus, the designing of hydrogels with MMP-2 responsiveness could improve the localized delivery of various drugs while reducing the side effects. Nevertheless, the major limitation of hydrogels for designing formulations for oral-related ailments is the encapsulation of hydrophobic drugs, limiting their applicability. Considering the advantages of smart hydrogels, one of the most effective methods to encapsulate hydrophobic drugs into hydrogels is to load them in their nanometric domains. In this vein, the nano-sized drugs offer uniform distribution and high dispersibility, improving the loading efficiency into hydrogels and avoiding side effects. Moreover, these hydrogel building blocks are often engineered using various chemical reactions for crosslinking during the fabrication in situ towards improved encapsulation of biological moieties, modulating hydrogel properties, and tailoring mechanical properties. In a case, collagenase-responsive HA hydrogels were designed for periodontitis to deliver nano GSK (GSK2606414) to inhibit the inflammation-induced expression of PERK in PDLSCs [218]. Initially, NanoGSK was encapsulated into hydrogels based on the Michael addition reaction between an MMP-2-cleaved peptide cross-linker (MMPc) and acrylated HA. Further, the in vitro and in vivo evaluation studies demonstrated that the overexpressed MMP-2 could release NanoGSK cargo in the gingival tissue of periodontitis, inhibiting inflammation-induced PERK and exhibiting exceptional alveolar bone repair capability. Considerably, these hydrogels with advantageous attributes present themselves similar to an ECM-like environment, facilitating the hydrophilic environment towards tissue growth. In another instance, Wen and colleagues fabricated mineralized hydrogel composites based on amorphous calcium phosphate (ACP) encapsulated polyacrylic acid (PAA)-carboxymethyl chitosan (CMC)-dentin matrix (TDM) [219]. The established dynamic network based on calcium and carboxylate ions loaded with TDM exhibited exceptional self-repair ability and improved injectability, promoting odontogenesis or osteogenic differentiation of mesenchymal stem cells. Despite the advantages, it is necessary to focus on exploring the colloidal stability of these polymeric constructs.

Dendrimers

Among various organic constructs, the class of dendrimers, coined from the Greek term dendron referring to “branching tree”, has emerged as highly ordered synthetic macromolecules manifested by a combination of compact molecular structures and diverse functional groups. These highly defined supramolecular architectures at a size of 1–15 nm are fabricated by sequential arrangement of various polymeric monomers into symmetric three-dimensional (3D) morphological structures. The defined shape and sphericity of dendrimers are attained by organized synthesis as branches of trees on a tiny core symmetrically. Although they belong to a family of polymers, these hyperbranched globular nanostructures are worth discussing separately, considering their spatiotemporal 3D arrangement of highly active functional groups rather than irregular assembly of traditional polymers. Unlike polymers that are synthesized by the polymerization reaction, these globular dendrimer structures are fabricated through a step-by-step process of altered functional groups successively into highly functionalized repetitive architectures, enabling the control over the eventual structure, for instance, polyamidoamine (PAMAM) dendrimers. Since the first dendrimers were fabricated, several efforts have been dedicated to exploring the generation of various 3D architectures involving the encapsulation of small molecules into nano-sized constructs. Considering these attributes, dendrimers have been explored in nanomedicine research for the delivery of drugs, including anti-cancer, antimicrobial, and anti-inflammatory, among others, for oral-based ailments [220].

Along this line, several dendrimers have been employed, including PAMAM [220], methyl methacrylate, and poly(epsilon-lysine) for oral applications, specifically drug delivery and in situ mineralization towards odontogenic potential, differentiation of osteoblastic cells, dentine restoration, and coating the implants [162, 220, 221]. Specifically, these dendrimers with various modifications with chemical functionalities like OH, –COOH, and –NH₂ terminal groups induce the regeneration of HA crystals, subsequently improving the remineralization and hardening of the acid-etched enamel, similar to the natural tooth. Owing to enhanced solubility and stability of small molecules, these dendrimers are entrapped with such moieties for improved bioavailability. In a case, Gardiner and colleagues enclosed triclosan in PAMAM dendrimers to enhance its solubility [220]. In addition, Tao and colleagues reported the generation of galardin-loaded PAMAM dendrimers, in which galardin inhibited MMPs to prevent collagen fibril breakdown, while NGV peptide improved collagen stabilization [222]. These dendrimers with dual collagen protection effects improve dentin remineralization, showcasing the efficacy of the anti-dentin caries in vivo. In another instance, Kim and colleagues presented PAMAM dendrimers functionalized with αVβ3-specific, cyclic arginine-glycine-aspartic acid (RGD) peptides to increase the odontogenic potential of dental pulp cells, resulting in the enhanced mineralization [162]. Moreover, these dendrimers could act as restorative vital substitutes in hard tissues, mimicking the non-collagenous proteins to promote mineralization. These features of improved performance in the oral cavity could be due to the enhanced mucoadhesive property and hyperbranched structure of dendrimers, enabling their comprehensive potential as a superior biomaterial for dental restorations and treatment of periodontal ailments.

Liposomes

Liposomes have become one of the versatile nanoplatforms that have been approved for clinical use. These lipid bilayer nanometric domains in the vesicular forms comprise amphiphilic precursors with a hydrophilic head and a lipophilic tail. These amphiphilic precursors are arranged in bilayers such that the lipophilic tails and hydrophilic heads are organized to form the inner aqueous core [223]. Interestingly, these bilayers can encapsulate hydrophilic components in the inner core and hydrophobic guests in the surrounding layer. These liposomal architectures offer several advantages, such as tailorable size and composition, modulating biodistribution towards controlling the drug delivery profiles. Considerably, these architectures stabilize the encapsulated therapeutic moieties by overcoming various challenges of minimizing systematic toxicity and improving cellular internalization at the cellular levels. Owing to their non-toxic nature and biodegradability, these liposomal-based therapeutic designs have been approved for the delivery of various drugs by the US-FDA, such as Doxil^® (doxorubicin), DaunoXome^® (daunorubicin), and Ambisome^® (amphotericin B), among others [224]. Considering these attributes, liposomal formulations have been designed to explore their therapeutic efficacy in improving oral health. In a case, a liposomal formulation was developed by encapsulating indocyanine green (ICG) and rapamycin composite nanoparticles into the 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) constructs for regulating the oral microenvironment [225]. These encapsulated nanoparticles significantly altered the oral microenvironment by producing excessive ROS and temperature towards hyperthermia, leading to eradicating the growth of two strains of bacteria (Fig. 8A) [225]. In addition, these composites prevent bacterial adhesion and biofilm growth, aiding the prevention of recurrence towards anti-microbial treatments. In addition to improved microbial-cellular interactions, these composites promoted macrophage M2 polarization, upregulating the anti-inflammatory effects promoting phagocytosis. Furthermore, these mechanisms were systematically demonstrated in an in vivo mouse model infected with S. oralis. Interestingly, the liposomal formulations presented exceptional bioavailability of the encapsulated ICG and rapamycin composite nanoparticles. Despite exploring the drug delivery and corresponding mechanistic views, it is imperative to examine synergistic actions towards improving oral health, such as drug delivery for anti-microbial characteristics and increased biomineralization. In an instance, the hydrophobic drugs (magnolol and fluconazole) were encapsulated in the Tris(tetra-n-butylammonium) hydrogen pyrophosphate-binding CHEMS-PEG₂₀₀₀-OH liposomes to over their hydrophobicity, achieving dual anti-bacterial activity against C. albicans and S. mutans [226]. In addition, these liposomal architectures offered exceptional hydroxyapatite binding ability, inhabiting acid resistance and biofilm formation towards treating dental caries.

Fig. 8

Reproduced with permission from Ref. [225] Copyright 2023, John Wiley & Sons. B Proposed concept of the bacteria-responsive micellar multidrug delivery system (PMs@NaF-SAP) targeting cariogenic biofilm. (i) Illustration of formulation and the bacteria-responsive activity of PMs@NaF. (ii) The modification of SAP and the formulation of PMs@NaF-SAP. (iii) Schematic illustration of topical application of PMs@NaF-SAP on dental plaque biofilm and proposed mechanism for caries prevention and enamel restoration. Reproduced with permission from Ref. [229] Copyright 2023, Elsevier

A Schematic diagram of the synthesis and effect mechanisms of indocyanine green (ICG)-Rapamycin: 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid bilayers encapsulate ICG and rapamycin to form nanoparticles. ICG-rapamycinmodulates microbial-cellular environments to perform the effects, which consist of elevating the ROS levels under an 808 nm laser excitation to achieve anti-bacterial effects, inhibiting bacterial adhesion from exerting anti-biofilm effects and promoting macrophage M2 polarization and bacterial phagocytosis to exert anti-inflammatory effects. In the mouse models of implant-associated infection and periodontitis, ICG-rapamycin performs treatment and prevention effects of the diseases by the modulation of microbial-cellular mechanisms.

In addition to conventional drugs and their composites, several essential natural molecules can be delivered directly into the oral matrix using liposomal formulations. Along this line, one of the MMPs critical for controlling the collagen in the oral ECM is collagenase, which can play a crucial role in the tissue remodeling process. This MMP is clinically approved for digesting abnormal thickening of tissues. To prevent undesirable damage, spatial control over the enzyme to act against the collagen-containing tissues is necessary. In a case, Zinger and coworkers designed proteolytic nanoparticles based on the collagenase type-I-encapsulated liposomal architectures as surgical tools for controllable remodeling of oral connective tissues [227]. The designed liposomal nanoparticles loaded with collagenase in a deactivated form were released orally and activated by calcium in the oral environment for periodontal remodeling. The remodeling process was recorded owing to the enzymatic cleavage of the supracrustal collagen fibers connecting teeth and underlying bone.

Micelles

Structurally, the micelles are spherical-arranged amphiphilic assemblies similar to the liposomal architectures in tens to hundreds comprising of hydrophobic core and hydrophilic shell. However, these architectures differ in their arrangement, as liposomes are arranged in a bilayer, while the micelles are in a single layer with hydrophobic groups in the core. Interestingly, the hydrophilic shell improves the water solubility of these architectures for biomedical applications. Specifically, hydrophobic drugs entrapped in the hydrophobic core are administered intravenously. Considering the spatiotemporal arrangement, these micelles can also be arranged in other shapes, such as cylinders, bilayers, and ellipsoids, among others. Owing to these interesting attributes, several micellar architectures have been designed for drug delivery for various diseases, including oral ailments. Indeed, dental caries often develop from tooth demineralization due to the acid production of bacteria plaques. Although several treatment options have been applied for reducing plaques and restoration of defects, it remains a challenge to identify and precisely interrupt the development of caries. In a case, Zhang and colleagues developed pH-responsive core–shell nano-sized micelles based on mPEG-b-PDPA to deliver bedaquiline, an anti-bacterial agent within an acidic biofilm microenvironment [228]. These biocompatible polymeric nanoparticles to the periodontal cells showcased exceptional bactericidal effects on mature S. mutans biofilm. Inspired by the dental plaque, Xu and colleagues demonstrated the fabrication of versatile bacteria-responsive micellar-based nanosystems (Fig. 8B) [229]. The spherical-shaped core–shell structures of micelles based on 3-maleimidopropionic acid-poly(ethylene glycol)-block-poly(L-lysine)/phenylboronic acid (MAL-PEG-b-PLL/PBA) were loaded with drugs (TA in NaF) for antibacterial and tooth restoration effects. The delivery system based on PMs@NaF-SAP was self-assembled by conjugating with salivary-acquired peptide DpSpSEEK (SAP), endowing the designed nanoparticles with strong adhesion to enamel and identifying cariogenic conditions to release drugs in acidic pH for antibacterial activity against S. mutans. Together, the topical treatment of designed composites in the rodent cariogenic model subsequently eradicated the onset and severity of caries without significant impact on oral microbe diversity. Despite the success, there exist some concerns on these delivery platforms in terms of colloidal stability while storage and administration, similar to liposomes and soft polymeric nano-sized hydrogels. Although the synthesis is based on critical chemistry, the designs predominantly dependent on the self-assembly approach, resulting in the uncontrollable size and lack of reproducibility.

Inorganic (synthetic) nanoassemblies

Owing to the exceptional physicochemical features and tunable morphological attributes, various inorganic nanoconstructs have garnered enormous interest from researchers due to their remarkable electronic architecture. Several capable examples of inorganic nanoparticles include semiconductors (ZnO and zinc sulfide, ZnS-based quantum dots, QDs), metallic nanoparticles (silver, gold, aluminum, copper, and platinum), magnetic and paramagnetic substances (iron and iron oxide, cobalt, and nickel composites) and miscellaneous constructs. Considering the tunable morphologies and based on various synthetic strategies, these inorganic constructs can be fabricated into multi-dimensional architectures ranging from 0D (semiconductors QDs, metallic nanoparticles), 1D (rods and wires), 2D (sheets), 3D (spheres and hollow, and cubes), as well as their nanoarchitectured composites. Due to their extensive surface-to-volume ratio and abundant surface chemistry, these inorganic composites in various architectural forms, specifically 0D, 1D, 2D, and 3D materials, can be utilized to encapsulate and deliver different anti-microbial drugs for improved anti-bacterial efficacy. Considering these attributes and enormous precursors, in this section, we present discussions related to inorganic-based synthetic nanoassemblies into architectural forms, highlighting their importance in delivering drugs and tissue remineralization abilities. Considering these attributes of exceptional physicochemical features and drug delivery efficacy, these inorganic-based nanoarchitectures have been applied for various dental-related ailments. While addressing various dental-related ailments, the inorganic materials, for instance, 0D and 1D-based materials, often act by themselves or by delivering different small molecular or supramolecular drugs for anti-microbial and remineralization efficacies. Usually, these 2D and 3D-based materials with remarkable encapsulation ability have been immobilized with various antibiotics and dispersed in the mouthwashes for anti-microbial characteristics. These anti-microbial features enable the treatment of various dental ailments, such as dental caries. In addition, several anti-inflammatory drugs (indomethacin and diclofenac) and chemotherapeutics (cisplatin and doxorubicin) can be delivered for treating oral ailments (specifically, gingivitis and periodontitis), as well as oral tumors in the buccal cavity, respectively.

0D quantum dots

Typically, 0D materials are referred to as nanodots with no critical dimension at an average size of less than 10 nm. Interestingly, these ultra-small-sized nanoparticles with innovative electronic architecture and surface-to-volume ratio outperform various dimensional structures towards specific applications, such as stimuli-responsive biomedical applications. However, some nanodots are toxic, hampering their utilization. Considering the dose-dependent toxicity, some classes of nanodots have been explored in various biomedical applications. Along this line, several kinds of nanodots have been employed for oral health, such as AgNPs. As one of the classic examples, these AgNPs act as anti-microbial agents by providing silver ions, enabling cellular death through various mechanistic ways [230]. In addition to delivering encapsulated small-molecular drugs, the specific electronic architecture of inorganic matrices with optical properties facilitates the light excitation ability towards photo-related bioefficacy, such as PTT and PDT. Often, these photo-activated materials activated by light act by increased temperature or free radical generation, resulting in improved anti-microbial efficacy. In an instance, Wang and colleagues demonstrated the generation of the inorganic-based alloy mixture of Au–Ag complexes coated with procyanidins for precision anti-bacterial and synergistic immunotherapy for periodontitis (Fig. 9A) [230]. The released silver ions contribute to PTT effects, achieving an excellent anti-bacterial effect and avoiding periodontal tissue damage towards synergistic anti-bacterial and anti-inflammatory immunotherapy. In addition to anti-microbial efficacy, some of these innovative architectures (silica-based and TiO₂) have been employed to act as remineralization products by delivering the necessary ions for the remineralization or regeneration of tissues. A classic example of these actions was the CaF-based nanoparticles (nCaF₂), which could provide Ca and F ions that were important for dental health in terms of mineralizing and restoring the tooth structure. Nonetheless, the release of ion release persistently remains highly challenging [231]. Although several antimicrobials are available, it is necessary to address their growth right from the formation of microbial colonization in the oral cavities and subsequent biofilm formation. In recent times, Liu and colleagues generated copper-doped nanodots to improve the infiltration of biofilms in the oral cavity [232]. These dots with catalytic (peroxidase- and catalase-like) activities of copper species in the oral environment substantially inhibited the adhesion and growth of bacteria (S. mutans) towards eradicating the initial stages of biofilm formation. In terms of inhibiting the proliferation of Gram-positive and Gram-negative bacteria (S. aureus and E coli), these composites not only improved wound oozing infection and promoted rapid wound healing but also enhanced the performance in terms of whitening, addressing the negligible enamel and dentin destruction.

Fig. 9

Reproduced with permission from Ref [230]. Copyright 2023, Royal Society of Chemistry. B TEM analysis of BNNP fabricated by a hydroxyl-assisted ball-milling process: (a) Low-magnification image to determine the lateral size, (b) High-magnification image of BNNP edge to confirm the number of layers. Reproduced with permission from Ref [234]. Copyright 2020, Elsevier. C Effects of calcium-based materials on hDPSCs mineralization. Photographs of mineral nodules formed after 28 days of culture. Representative pictures of Alizarin Red S-stained assessed with transmitted light microscopy at 20 × magnification are shown (i). Quantification of Alizarin red staining (ii). The result was representative of three different experiments. ** indicates P < 0.01, and *** represents P < 0.005 versus CTL. Reproduced with permission from Ref. [235] Copyright 2023, Elsevier. D Simplified schematic diagram of nZnO/MTC-Ti regulating Zn²⁺ release, osteogenesis, and antibiosis. E Osteogenic differentiation of BMSCs cultured on various Ti substrates: fluorescent staining images of OCN in the cytoplasm of BMSCs on various samples. Reproduced with permission from Ref. [236]. Copyright 2023, American Chemical Society

A Schematic illustration of AuAg-PC NPs in the principle of synthesis and therapeutic mechanism in the treatment of periodontitis.

1D structures

Owing to a high aspect ratio, the fabrication of 1D nanostructures offers exceptional synergistic functionalities in terms of thermal, morphological, and optical, among other physicochemical properties. Moreover, these architectures with high aspect areas offer an elongated surface that facilitates improved adhesion to the biological surfaces towards enhanced penetration. The peculiar kinds of 1D nanostructures include nanorods and nanotubes, offering improved delivery of drugs towards enhanced therapeutic efficacy [118]. Specifically, the nanotube topography as a surface could lead to improved antibacterial properties, which, however, showed contrary findings in some other instances [118]. In one case, Kunrath and colleagues demonstrated the fabrication of a nanotextured surface (TiO₂ nanotubes) from pure Ti, which was then coated with PLGA and loaded with rifampicin [119]. These innovative architectures at an arbitrary range (macro to nano-sized constructs) could be applied for coating the dental implant platforms towards improved antibacterial efficacy. Several molecular and microbiological assays were performed to demonstrate and compare biological properties among these developed surfaces among various size ranges. Importantly, the hydrophilic surfaces presented optimal properties for intra-osseous surfaces, resulting in the potential characteristics to act against early contamination in the mucosal region. To a considerable extent, it would be nevertheless challenging to internalize the biofilm due to highly proteinaceous architectures. Considering these aspects, Tang and coworkers designed an innovative therapeutic platform, i.e., a material-assistant micro-organism (MAMO) strategy, as a countermeasure based on ZnO nanorods-engineered Bdellovibrio to remove plaque biofilm in the oral cavity [233]. These ZnO nanorods with piezoelectric material could produce ROS by sensing mechanical pressure. Bdellovibrio adhered with ZnO nanorods, which could collide, realizing the generation of ROS during the predation process and removing the biofilm effectively. In addition, these composites could substantially alleviate inflammation and inhibit bone resorption in rats and rabbit periodontitis models.

2D nanoplates

The 2D materials are plate-like thin structures that possess a larger transverse area, offering enormous contact surface area with improved encapsulation efficacy of guest species compared to the low-dimensional materials, such as 0D and 1D materials. After the discovery of a classic example of graphene nanosheets, several efforts have been dedicated to fabricating various 2D materials, including transition metal-based dichalcogenides (TMDCs), MXenes, and layered double hydroxides (LDHs), among others [33, 34, 237]. Although coprecipitation and hydrothermal methods have been applied for the synthesis of 2D materials, the exfoliation-based top-down approach has emerged as one of the classic techniques to generate various 2D sheets with thickness, including mono-layered paper-like constructs. In an instance, Lee and colleagues fabricated boron nitride (BN) nanoplatelets by exfoliation h-BN using high-energy ball-milling and dispersion on a zirconia matrix (Fig. 9B) [234]. Several mechanical properties in terms of fracture toughness (~ 27.3%), flexural strength (~ 37.5%), and wear resistance were explored. This mild-temperature-assisted degradation of nanoplatelets showed exceptional biocompatibility, which could possess potential as reinforcement materials for dental ceramics. In another instance, Aati and colleagues fabricated graphene-based nanoplatelets and encapsulated at different concentrations [0.0, 0.025, 0.05, 0.1%, and 0.25% (w/w)] into acrylate-based resin to generate 3D printed resin-based composites for improved oral health [238]. These composites at a GNP concentration of 0.25 wt% enhanced printed nanocomposite hardness and elasticity. In addition to the biocompatibility attribute with oral fibroblasts, these composites showcased antimicrobial activities against C. albicans. Similarly, Hu and colleagues employed the recently emerged 2D MXene (Ti₃C₂T_x) nanosheets into the epoxy resin at altered mass ratios using the solution blending approach for practical dental applications. Interestingly, these as-fabricated MXenes in resin composites improved the mechanical properties compared to pure resin. In addition, these biocompatible nanocomposites against normal cells presented exceptional anti-bacterial activity after irradiation with natural light owing to their photothermal efficiency.

Although some studies have demonstrated the efficiency of 2D materials, it is imperative to explore the sole performance efficacy rather than a support material in resins. Nevertheless, some of the resin surfaces would result in secondary caries around the restoration of the oral cavities, requiring promising antibacterial material. To address this aspect, Li and colleagues fabricated ZnO nanorods-decorated graphene oxide composites for their application in dental resins [239]. These composites were fabricated using a facile hydrothermal method by changing the amount of seeded GO. The designed GO₃@ZnO-filled composites resulted in not only exceptional flexural strength and modulus but also resulted in the inhibition of S mutans compared to unmodified resin. These functional composites with promising physical–mechanical performance could be employed in dental fillers.

3D architectures

Compared to various low-dimensional (0–2D) architectures, the 3D nanostructures in the sub-micron range (10–1000 nm) have garnered enormous interest owing to their exceptional physicochemical and morphological attributes. Specifically, these nanoconstructs with porous architectures can be of particular interest in the encapsulation of various guest species (drugs, proteins, and genes). In addition, several inorganic precursors, such as silica and ZrO₂-based, can be applied to fabricate various porous architectures (hollow and core–shell) for encapsulating the inorganic components for antimicrobial effects [240, 241]. In this case, zirconia (ZrO₂)-based spherical composites were fabricated as dental fillers using microwave-assisted synthesis and doped with the Fe₃O₄ nanoparticles [240]. The authors demonstrated that the microwave energy dissipation resulted in the volume shrinkage of nanocomposites, which showcased the exceptional anti-bacterial effect of the doped Fe₃O₄ against Bacillus species towards acting as potential dental fillers with anti-microbial efficacy. In another instance, carbon dots-embedded silica nanoparticles were employed as non-destructive teeth-whitening agents [241]. These composites facilitated the passage of energy through the intersystem crossing (ISC) approach, thus encompassing the half-life of ROS towards thoroughly whitening teeth by reducing stains on the enamel.

In addition to improved anti-microbial efficacy and whitening, the tissue regeneration ability of the designed inorganic nanocomposites has been demonstrated using diverse precursors. Although the regeneration ability of polymers is profoundly explained, it is scarce in the case of inorganic composites due to toxicity issues and challenges in the fabrication of scaffolding constructs suitable for tissue growth. However, these inorganic components can offer specific physicochemical functionalities that can potentiate growth by improving the biochemical and mechanical cues. Nevertheless, the regeneration ability of various Ti-based/Ca-based implants has been explored in recent times. In an instance, Spagnuolo and coworkers demonstrated the ability of calcium-based materials (CaCO₃, Ca(OH)₂, and mineral trioxide aggregate (MTA)) in differentiating hDPSCs to odontoblastic-like cells by expressing specific odontogenic-related genes (Fig. 9C) [235]. These calcium supplements, specifically MTA, better than CaCO₃, Ca(OH)₂, resulted in the increased ALP activity and differentiation marker, matrix extracellular phosphoglycoprotein (MEPE), towards regenerative purposes. Nevertheless, dental implants as fillers or for regeneration lack biological effectiveness, increasing the cases of peri-implantitis. In a case, Wen and colleagues fabricated zinc oxide (ZnO) nanoparticles loaded on mesoporous TiO₂ coatings using the evaporation-induced self-assembly (EISA) approach (Fig. 9D) [236]. These composites, with sustained release of Zn²⁺ ions and subsequent transport through modulation of zinc transporters (ZIP1 and ZnT1), enabled their superior anti-microbial activity. Regulating the release of Zn²⁺ ions through proper channels substantially addressed their biocompatibility, promoting the osteogenic efficacy of BMSCs (Fig. 9E). Moreover, the accelerated osseointegration, antibiosis, and improved anti-bacterial action of nZnO/MTC-Ti implants facilitated improved performance efficacy in SD rats in vivo after tooth extraction.

Despite the success in the development of these innovative and highly stable architectures, most of these designs have been restricted to being applied as implants due to a lack of bioefficacy, leading to a risk of peri-implantitis. Further efforts are required to explore different alternative composites with improved anti-microbial effects and address their compatibility issues. Moreover, it should be noted that not all the inorganic constituents are stable, as ACP often suffers from instability issues, limiting its clinical application [242]. It is suggested that some composites be prepared that can improve their ability to release ions towards hard tissue mineralization. Along this line, several critical limitations of these inorganic assemblies include the risk of poor degradability-associated compatibility, hampering their clinical application. Although these constructs are feasible for the fabrication of remineralized products and dental implants in edentulous conditions, they are strictly required to address other dental-related ailments, specifically, providing the anti-microbial characteristics and regeneration of soft tissues in oral-based diseases.

Supramolecular (organic–inorganic) composites

Typically, the designed organic and inorganic-based constructs solely suffer from various individual limitations. For instance, organic materials pose stability issues from the colloidal point of view. Contrarily, the colloidally stable inorganic-based assemblies suffer from degradability issues. Considering these limitations of inorganic and organic species solely, several efforts have been dedicated to fabricating hybridized materials based on supramolecular organic–inorganic composites, either organic moieties-coated inorganics or inorganic-deposited organics, for treating oral ailments, such as secondary caries. These supramolecular assemblies of organic and inorganic constructs accommodatingly support each other in addressing their limitations [243, 244]. In this section, we further discuss the diverse arrangement of various organic and inorganic constructs for different dental ailments. For a better understanding, we present the discussions on these organic and inorganic-based composite constructs in terms of various size ranges, for instance, small-sized or sub-micron-ranged organic-coated inorganic nanoparticles or vice versa, for drug delivery and large-sized (micron-ranged) constructs coated with one over the other, or vice versa for synergistic implantable dental applications towards tissue regeneration.

Organic-coated over inorganics

Considering the flexibility and convenience of synthesis, it is feasible to coat organic layers on the rigid inorganic species extensively. Specifically, inorganic-based materials (Ag, Zn, barium titanate, BaTiO₃, and Ti) offer anti-microbial effects, and some possess remineralization (Ca and PO₄³⁻) effects. The organic moieties are encapsulated with various inorganics, including chitosan, poly(carboxybetaine acrylamide) (PCBAA), PDA, polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), and poly(allylamine hydrochloride) (PAH), among others [7, 243, 245]. Accordingly, fabricating these precursors into diverse composites has garnered specific interest from researchers, in which metal ions are either doped in polymers or their nanoparticles coated with organic polymers. In a case, Javed and coworkers fabricated chitosan-coated ZnO nanocomposites (average size of 30 nm), presenting exceptional mechanical properties and remarkable reduction in the growth of S. mutans and L. acidophillus strains [246]. In another instance, Yi and colleagues fabricated yolk-shell architectures based on the silica-coated mesoporous titanium–zirconium nanocarrier, which was then coated with the PAH-stabilized ACPs (Fig. 10A) [247]. These composites improved the dentinal tubule occlusion, inducing the remineralization of demineralized dentin matrix and intrafibrillar mineralization of single-layer collagen fibrils. Similarly, Yu and colleagues fabricated a hybrid nanoplatform based on encapsulating epigallocatechin-3-gallate (EGCG) and PAH-ACP co-delivery using hollow mesoporous silicas (E/PA@HMS). These abrasion-resistant nanovehicles effectively occluded dentinal tubules and inhibited the biofilm of S. mutans (Fig. 10B) [7]. In addition, the surgical removal of OSCC often results in facial deformities and impaired oral function. Although radiotherapy has been predominantly applied as a primary non-invasive therapy to avoid surgical-based limitations, the lack of specificity hampers its applicability due to deprived radiation tolerance of normal tissues in the oral microenvironment and hypoxia-induced low radiosensitivity of tumors. In a case, Gu and coworkers fabricated mussel-inspired tantalum nanocomposites for OSCC treatment (Fig. 10C) [248]. Initially, the tantalum nanoparticles were encapsulated in PVP and deposited in dopamine acrylate (DAA) hydrogels. PVP encapsulation substantially augmented the X-ray deposition ability towards improved oxidative stress and improved hypoxia for tumor radiosensitivity. These hydrogels with catechol and bioadhesive features improved the precision radiotherapy of the composites in vivo (Fig. 10D–F).

Fig. 10

Reproduced with permission from Ref [247]. Copyright 2023, Royal Society of Chemistry. B (i) Schematic illustration of EGCG and PAH-ACP co-delivery hollow mesoporous silica (E/PA@HMS) nanosystem for synergistic management of exposed dentin. (ii) The exposure of dentinal tubules is susceptible to external stimuli and cariogenic bacterial attack, thereby leading to dentin hypersensitivity, caries, and pulp inflammation. (iii) The application of E/PA@HMS can durably occlude the dentinal tubules with acid-/abrasion-resistant stability and remineralization effects. Reproduced with permission from Ref. [7] Copyright 2023, KeAi Publishers. C Design thought of DAA hydrogels and Ta@PVP-DAA hydrogels. D Digital images of Ta@PVP NPs and Ta@PVP-DAA hydrogels in OSCC. E Fluorescence images of Ta@PVP NPs, Ta@PVP-ALG hydrogels, and Ta@PVP-DAA hydrogels in OSCC. The above-used Ta@PVP constructs are marked with Cy5. F CT images of Ta@PVP-DAA hydrogels in OSCC. Reproduced with permission from Ref [248]. Copyright 2023, American Chemical Society

A (i) Schematic illustration of the synthesis process of STZ and PSTZ. (ii) TEM microphotographs and corresponding elemental mapping of STZ and (iii) PSTZ.

Despite the development of various successful formulations in addressing these dental ailments, most of them fail to achieve clinical status due to multiple factors, such as poor performance efficacy, as well as resultant deprived physicochemical and mechanical features. The predominant reason is that the bacterial infection forms biofilm, results in the demineralization of the hard tissue, and damages the composite and eventual tissue architecture. To address these issues together, BaTiO₃-based piezoelectric nanoparticles were developed as a multifunctional bioactive filler in dental resin composites, offering subsequent anti-bacterial and remineralization efficiencies. These dental piezoelectric resin composites improved the physicochemical properties of resin and inhibited 90% of biofilm growth, forming the calcium phosphate minerals in piezoelectric composites. Interestingly, these large-sized composites validated the bond strength of dentin-adhesive-composite interfaces, providing long-lasting, non-rechargeable anti-bacterial/remineralization properties [249]. Xu and colleagues demonstrated the fabrication of oral microenvironment responsive release of metal-phenolic (copper tannic acid coordination nanosheets, CuTA NSs) components encapsulated in the hydrogel network based on triglycerol monostearate/2,6-di-tert-butyl-4-methylphenol (Fig. 11A) [250]. This innovative design offered improved resident time of enzyme, reduced dosage, and on-demand release of hydrophobic drugs, as well as favorable compatibility. In addition to reducing the oral anti-microbial effects, these innovative constructs improved the anti-inflammatory effects by regulating the Nrf2/NF-κB pathway and transforming M1 macrophages to M2 macrophages. Moreover, the expression of osteogenesis genes enunciated the accelerated regeneration of periodontal tissues towards the synergistic treatment of periodontitis (Figs. 11B–D). In another case, cobalt-ferrocene MOFs with strong Fenton reactivity were fabricated to act against OSCC with MDR (Fig. 11E) [251]. These MOFs were encapsulated with hydroxychloroquine and subsequently coated with the oral cancer cell membranes extracted from the CAL-27 cell line. The experimental results demonstrated exceptional tumor targeting effects, biosafety, and augmented therapeutic effects. Interestingly, these composites presented local autophagy ROS boosting towards ablating OSCC cells. In addition, a multifunctional coating using gelatin and /hydroxyapatite nanoparticles on Ti foils was performed, and the effects on cell adhesion, proliferation, and anti-bacterial effects were studied [252]. As anticipated, the cells deposited on these films showcased improved anti-bacterial effects against S. mutans, as well as cell attachment and osteogenic differentiation effects of the PHG-coated surfaces.

Fig. 11

Reproduced with permission from Ref [250]. Copyright 2023, American Chemical Society. E) Conceptual schematic diagram of the preparation process and intracellular mechanism of CM@Co-Fc@HCQ nanoparticles. Reproduced with permission from Ref [251]. Copyright 2023, John Wiley & Sons. F) Schematic illustration of the PCBAA/ACP nanocomposite with dual antibiofilm and remineralization functions, and evaluation of the effect of the PCBAA/ACP nanocomposite on inhibiting cariogenic bacterial adhesion and biofilm formation on the enamel surface and promoting enamel remineralization (including surface and subsurface lesions) and DT occlusion. Reproduced with permission from Ref. [242] Copyright 2022, American Chemical Society

(A) TM/BHT/CuTA hydrogel was used to self-assemble the CuTA nanozyme, TM, and BHT to treat periodontitis. (B, C) The negatively charged TM/BHT/CuTA exhibited long-term retention at the inflammation sites with a positive charge through electrostatic adsorption. (D) The released CuTA nanozyme exhibited antibacterial effects on bacteria associated with periodontitis.

Inorganic-coated over organics

Owing to exceptional physicochemical attributes, various inorganic species have been coated on the organic constructs to fulfill the anti-microbial and tissue regeneration applications. Although it is quite challenging to fabricate inorganics on organic species, several researchers have explored the applicability of rigid inorganic nanodots on flexible organic macromolecular constructs for dental applications. In a case, Liu and colleagues fabricated thermoplastic poly-merpolyetheretherketone (PEEK) discs coated with nanosilver at varied thicknesses (3, 6, 9, and 12 nm) magnetron sputtering technology [253]. These nano-silver-coated compatible architectures not only improved the bacterial adhesion efficacy but also offered antibacterial efficacy against S. mutans and S. aureus. In addition to anti-microbial effects, remineralization approaches have been used to supply various essential ions, such as Ca²⁺ and PO₄^3– through amorphous calcium phosphate (ACP) constructs. In most instances, the ACP constructs suffer from instability, limiting their clinical application due to the lack of undesirable biofilm formation. For instance, He and coworkers fabricated the zwitterionic composites based on PCBAA and ACP to execute remineralization and antibiofilm properties (Fig. 11F) [242]. These composites also exhibited exceptional inhibitory effects on the biofilm formation of S. mutans under acidic conditions. In comparison to fluoride formulation, the designed dual-functional composites presented superior remineralization effects of demineralized enamel. Similarly, Dai and coworkers demonstrate the fabrication of an amorphous calcium phosphate nanocomposite with epigallocatechin gallate to interrupt the cariogenic biofilm formation during remineralization. These synthesized nanocomposites were highly compatible with L929 and human gingival fibroblasts, indicating their biosafety attribute. The sustained release of ACP from the designed EGCG-ACP composites exhibited substantial anti-bacterial effects and restored the demineralized enamel with improved microstructure and mechanical properties. Accordingly, these composites provided a theoretical basis in caries risk applications.

As mentioned earlier, the conventional precursors from organic and inorganic sources are assembled by coating one over the other, considering the performance and delivery applications. Although several kinds of hybrids have been fabricated systematically, in some instances, the combination of multiple components has been designed to improve the applicability of the single components. In an instance, Mayorga-Martinez and colleagues fabricated magnetic photoactive microrobots based on ferromagnetic (Fe₃O₄) and photoactive (BiVO₄) materials self-assembled using the PEI micelles to eradicate biofilm growth on a dental implant towards improving the subsequent formation of gingivitis and implant loss [254]. Initially, PEI-coated Fe₃O₄ composites were encapsulated with BiVO₄ through the self-assembly process. The enclosed Fe₃O₄ materials could propel under a transversal rotating magnetic field, while the BiVO₄ produced excessive ROS to eradicate biofilm colonies by 90% in the oral microenvironment. Interestingly, these actively driven ferromagnetic species enable the homogenous distribution of oxidative species by BiVO₄. Notably, these magnetically powered microrobots could precisely navigate toward biofilm destruction on titanium alloy-based implants. In another instance, Chen and colleagues fabricated a multi-component system based on the metal-phenolic networks with Pd nanoparticle nodes (MPN-Pd) for eradicating oral microbial biofilm-associated infections [255]. These Pd nanoconstructs stabilized in a polyphenol network through coordination linkages were reduced to nanoconstructs to inhibit their aggregation. These nanoparticles could be conducive to the reduction of O₂ on the surface, essentially generating the near-infrared (NIR)-induced hyperthermia towards ablating S. mutans and Enterococcus Faecalis (E. faecalis) via its oxidase-like property, eradicating oral polymicrobial biofilm-associated infections. Although the design sounds interesting, it is necessary to explore the optimization of various inorganic components to avoid severe aggregation. In addition, comprehensive biosafety investigations must be performed to investigate their further translation.

In some instances, these exquisite nanoparticles would act on reducing the bacterial infection, limiting the protection to resin-dentin bonded interface in terms of persistent apical periodontitis and lacking remineralization. In an attempt to protect the resin-dentin bonded interface, Toledano and colleagues fabricated PolymP-n Active (2-hydroxyethyl methacrylate, a cross-linker, ethylene glycol dimethacrylate, and a functional monomer, methacrylic acid) nanoparticles encapsulated with zinc and doxycycline [256]. The authors applied disks, which were exposed to a cariogenic biofilm challenge in a drip-flow reactor, for 72 h and 7 d. The Zn-doped polymeric nanoparticles resulted in exceptional anti-microbial efficacy, inhibiting the biofilm formation and the highest mineralization degree in accordance with the phosphate levels. Although the actions are limited by the pristine organic constructs, the combination of Zn and polymers resulted in synergistic anti-bacterial and remineralizing effects against cariogenic biofilm in vitro. In addition, the doxycycline-loaded PolymP-n Active nanoparticles resulted in the scaffolding of collagen but not remineralization. Similarly, they demonstrated the fabrication of melatonin-doped PolymP-n Active nanoparticles to decrease dentin permeability and ease dentin remineralization after endodontic treatment [257]. These melatonin-doped nanoparticles presented higher functional remineralization than the undoped nanoparticles. In another instance, the authors loaded dexamethasone and zinc-loaded nanoparticles to reinforce and remineralize the coronal dentin [258].

Dental implants

Typically, various dental-related ailments eventually result in the edentulous pathological condition, referred to as tooth loss, resulting in the further destruction of the oral cavity. To improve oro-dental conditions, various dental ailments, such as cracked teeth and complete tooth loss, can be treated by replacing voids surgically with certain dental implants, which can look and function like real teeth [240, 259]. Moreover, the surgical procedures are employed for establishing dental implants towards building the bridgework for tooth replacements. Nevertheless, dental implants must be considered based on the condition of the jawbone and the type of oro-dental condition. These implants offer solid support for the new teeth, requiring the bone to heal around the implants. Moreover, it facilitates the treatment of damaged tooth removal, jawbone preparation, bone growth, and eventual healing of the injured sites. Although these dental implants are way too large and fall outside of the scope, it is worth noting that they require some surface modification using various nanoengineering strategies for improved osseointegration purposes.

Several kinds of dental implants include titanium, porcelain, ceramics, and zirconium-based materials. Among them, porcelain titanium has emerged as one of the most common dental implants due to its ease of implantation in the jawbone. Moreover, the implantation of dental matrices often poses various challenges of inappropriate fixation and infection at the implantation site, as well as undesirable injuries, leading to nerve damage and sinus problems, among others. In addition to expert views and critical examination prior to implantation, the medical treatment plan should be appropriately planned using implants with improved performance. Considering these challenges of undesirable infections and abridged osseointegration, several surface treatments based on plasma and chemical-etching treatment approaches have been employed to modify their surfaces, altering their morphology, roughness, wettability, and compatibility, among other attributes. These treatments often involve atomic scale modifying the surfaces of the implant materials, improving the cell adhesion towards regeneration and osseointegration of implants. In this context, Ti, Ag, silica, and aluminum oxide (Al₂O₃) nanoparticles have been deposited using the acid-etching approach on the implant surfaces [130, 236, 240, 260]. In most instances, the coating of metallic nanocomposites improved the antibacterial efficacy of the dental implants [130, 261]. In a case, silver ions were released continuously from the Ag-TIPS-Ti surface for 7 d, causing remarkable anti-bacterial activity over 12 h of culturing [130]. However, these composites exhibited no severe cytotoxicity against fibroblast cells for up to 10 days, indicating their biocompatibility. In addition to anti-bacterial efficacy, some studies explored the importance of pretreatment towards improving osseointegration. In another case, the pretreatment of dentin with bio-nano complexes based on the enamel protein amelotin (AMTN) before adhesive application significantly improved shear bond strength, accelerating the mineral formation and collagen mineralization of bio-nano complexes [260]. Despite the improved performance of the implants, these strategies suffer from various limitations. Predominantly, nanocasting of various metallic layers over the traditional implants requires additional sophisticated processing. In addition, the osseointegration without any signs of cytotoxicity is merely challenging as some elements may pose accumulation-induced toxicity risks, requiring extensive comprehensive investigations. Finally, the long-term behavior of these nano-casting surfaces remains unexplored extensively against biomedical applications.

Challenges

In the past decade, the exploration of nanotechnology and related biomaterials has become exceptionally crucial in various areas of the biomedical field, including dentistry. Although extensive research has demonstrated the exploration of treating various oro-dental ailments (periodontitis and oral tissue engineering) using various nanotechnologies, it is quite challenging to translate these innovative nanoarchitectures to the commercial market [262]. There exist numerous reasons concerning the challenges of developing nanomaterial-based drug delivery systems, such as the requirement for innovative approaches to several biomaterials. Although the research and preclinical outcomes are satisfactory, various features of the developmental stage pose predominant challenges, including synthesis, analysis, safety, sterilization, and storage requirements [263]. In this chapter, we discuss the challenges faced by these innovative technologies and their products.

Typically, the demand for the rapid exploration of various strategies has pushed researchers toward the development of various innovative nanotechnologies for drug delivery and engineered dental implants. The predominant innovative explorations include the generation of nano-sized ultrasmall constructs for delivering drugs towards improving solubility and the integration of such nanotechnological products with conventional biomaterials for therapeutic achievements at the molecular levels [264]. Typically, the challenges concerning the synthesis of these nanomaterials include various aspects of preparation, equipment requirement, reproducibility, and cost and time constraints. The fabrication of nanomaterials is quite complex and diverse, requiring the facile and commonly applied synthesis method. Although several chemical-based facile approaches are quite convenient for synthesizing different innovative structures, most of the synthesis methods require enormous amounts of solvents, damaging the environment [36]. Accordingly, it is essential to develop eco-friendly techniques, such as supercritical fluid technology. Moreover, some of the precursors for the generation of nanoparticles are highly expensive, requiring the development of cheaper sources to reduce the cost of production on a large scale. Concomitantly, the generation of nanostructures is challenging to produce uniform-sized architectures with reproducibility, quite dissimilar to traditional drug delivery systems. Moreover, the encapsulation of various small molecules (antibiotics/anti-cancer/anti-inflammatory) are another challenging to reproduce the similar loading efficacy during the fabrication of nanoparticle-based delivery systems consistently. Considering these critical aspects, it is quite difficult to reproduce nanoparticle-based biomaterials for oro-dental ailments. In addition to typical nanoparticles, several metallic nanoparticles have been integrated with the dental implants, which can be employed for the anti-bacterial application for biofilm eradication and killing resistance bacteria in periodontal conditions and subsequent tissue regeneration successfully through osseointegration. The classic examples include coating Ag on Ti implants and metallic constructs (Ag, Sr, and Au) encapsulated with polymeric (hydroxyapatite and chitosan) constructs [264]. Along this line, various physicochemical approaches, such as laser vaporization, chemical vapor deposition, and spray-drying, among others, have been applied to fabricate these metallic nanoparticle-integrated implants [265, 266]. Nevertheless, the performance efficacy of such innovative nanocomposites on a large scale remains unexplored, requiring comprehensive investigations.

Further, the immediate step after synthesis is the evaluation of the designed innovative nanoarchitectures concerning their responses at the cellular level from the biological point of view. Although the research explorations have been demonstrated in most instances using in vitro and in vivo models, several reports indicated that these findings could fail to replicate the biological responses of these innovative biological materials due to the complexity of oral bone and periodontal tissues in human and large animals, such as osteoporosis and periodontitis, among others [267]. Along this line, several tissue models mimicking the 3D microenvironments and stem cell engineering have been employed to simulate the physiology of organs and tissues of the oral tissues [268]. In this regard, several investigations are required to be explored, along with the reproducibility of multiple species prior to clinical trials and their translation. Despite no complete replication between humans and animals in terms of absorption and metabolism, these studies applying larger animals and comparing them with small-sized animals can be no distant from human physiology [269]. Similar to bioefficacy, the biosafety of any nanoparticle-based delivery system is important, and it plays a major role in their approval and subsequent applicability in terms of patient compliance. Although the biosafety investigations ranging from cytocompatibility in 2D cultures in vitro and hemocompatibility in blood or tissue compatibility by various staining techniques, the altered tissue organization and their responses, as well as genotoxicity at the molecular levels, must be explored comprehensively. In addition to safety and efficacy attributes, degradability, which goes hand-in-hand with safety and excretion attributes, of any nanoparticle is extremely important to consider, requiring investigations in terms of exploring the degradation kinetics [270]. These comprehensive evaluations eventually influence the final bioefficacy and subsequent clinical translation of the delivery platforms.

Finally, the sterilization and preservation attributes of the designed dosage forms are quite equally important as their optimization/synthesis or bioefficacy/biosafety attributes of any delivery platform [264]. Several sterilization approaches are available to prevent contamination that might influence the findings in the cells and animal models [271]. Nevertheless, no detailed information is available on the sterilization of these biomaterials, requiring the comprehensive exploration of these investigations and their patent reports. Importantly, the applicability of various metallic or organic-based composites often requires altered sterilization conditions to avoid critical damage. Accordingly, the lack of detailed protocols and standard procedures usually leads to confusion among researchers or R&D personnel while determining the protocols. These attributes often require the dearth of information to overcome the massive gap in translating these innovative biomaterials for oro-dental applications [264]. After sterilization, the packing and durability should be considered, as the packed materials might influence the product, resulting in abridged therapeutic outcomes. Typically, the packing materials must not be prone to oxidation with enhanced shelf-life, increasing their protection with the coating materials till their application in the market.

Outlook and prospects

In summary, this article has provided a comprehensive overview of different nanoarchitectured composites for dental ailments. Initially, we presented various bothering dental-related diseases, such as gums-, tooth-, and oral-related ailments, highlighting detailed pathological circumstances and their effects on human health and deficiencies with the currently available conventional therapeutic modalities. Further, various nanostructured components are important in addressing severe dental-related issues. In addition, a brief note on different syntheses was provided, exploring the effects of multiple parameters on morphological and physicochemical features. Finally, various nanoarchitectured composites as therapeutic solutions are discussed, including natural components and other organic- and inorganic precursor-based constructs for improving dental health by providing substantial anti-bacterial, remineralization, and tissue regeneration abilities.

In terms of various nanoarchitectured composites used for dental ailments, the predominant nanostructures include multiple carriers for the delivery of anti-microbial/anti-inflammatory/anti-cancer therapeutics. Notably, most dental-related illnesses initially start with bacterial infections and successive biofilm formation, eventually leading to a critical dental ailment. Applying various antibiotics to treat such bacterial infections has resulted in global concerns about developing antibiotic resistance. Owing to these aspects, it is suggestible to use anti-bacterial materials based on external stimuli in terms of drugless or drug-like carriers for augmented anti-microbial therapeutics. However, strict optimization of various synthesis parameters is required to be explored, followed by comprehensive evaluations of substantial compatibility and toxicity attributes toward long-term effects. Considering the development of various anticaries and regenerative materials, most of the attributes remain to be explored towards their clinical translation. In most instances, researchers have exploited the development of different innovative constructs addressing the anti-microbial actions and their subsequent remineralization effects. Nevertheless, understanding the interactions between the composites or implants and the infections is inevitable to address them comprehensively. Although some materials have shown exceptional differentiation and successive regeneration ability, the comprehensive mechanistic explorations at the molecular levels are yet to be investigated in terms of utilizing various inorganics and organics, as well as their composites. Together, we believe that exploring these prospects will substantially pronounce their usage to demonstrate the full potential of these nanoarchitectured components for dental health.