Table 4 Direct modification of EBPs

Folic acid

RAW264.7

Photosensitizer protoporphyrin X (PpIX) + DOX

Incubation

Folic acid (FA)

Incubate with DSPE-PEG-FA

Focusing on tumor tissue

Prodrug conversion combined with photodynamic therapy

[101]

E.coli BL21

ICG

Incubation

Calcium phosphate nanoshell (FA modified)

Incubate with calcium chloride solution

The PH-sensitive shell responded to the tumor environment

[28]

HEK293T

FA-3WJ-survivin siRNA-A647

Incubate with DSPE-PEG-FA

siRNA carried by vesicles can avoid being captured by inclusions

[102]

HT29

DOX

Incubation

EpCAM-MNPs/DSPE-PEG-FA

Incubate with DSPE-PEG-FA

Improved biocompatibility, induced hyperthermia and inhibited tumor growth

[103]

Colostrum

Paclitaxel

Incubation

FA

Activated FA by EDC and NHS covalently attaching

Overall efficacy and safety were improved compared with traditional administration

[17]

HEK293T

ICG

Incubation

FA

Activated FA by EDC and NHS covalently attaching

Sonodynamic therapy for antitumor

[104]

Polypeptide

ReNcell VM

Cholesterol-conjugated siPDL1

Incubation

c(RGDyK) peptide

Copper free click chemistry

Targeted integrin αvβ3 on cerebrovascular endothelial cells

[91]

Human plasma

Imperialine

Soluplus solubilization + ultrasonic

CC8

Incubate with CC8-Mal-PEG-CLT

Targeted integrin α3β1 overexpressed in non-small cell lung cancer

[93]

Mouse blood

Multifunctional chimeric peptide

Ice-water bath

Cytoplasmic membrane targeting combined with nuclear targeting photodynamic therapy

[105]

Nude mouse macrophages

Legumain-specific propeptide of melittin (legM) + cytotoxic soravtansine (DM4) prodrug

Incubate with DMPE-PEG

Targeted the tumor microenvironment and performed prodrug transformation

[106]

L929

MTX

lipid-KLA-LDL peptide

Incubation

Promoted apoptosis and selectively bound BBB and GBM cell lines

[107]

cisplatin-resistant human ovarian cancer cell line SKOV3-CDDP

Triptolide + miR497

Mix in CaCl₂ solution

cRGD-modified liposome

Ultrasonic + extrusion

Overcame cisplatin resistance, promoted intracellular ROS production, and induced macrophage polarization from M2 to M1

[108]

Raw264.7

SPION + curcumin

Electroporation

RGERPPR peptide (RGE)

Cycloaddition reaction of sulfonyl azide

Targeted glioma cells and tumor vascular endothelial cells

[73]

Antibody

Raw264.7

AB680

Extrusion

aPDL1-PEG-DSPE

Incubation

Anti-PD-L1 therapy combined with CD73 inhibitors had a stronger anticancer effect

[109]

HEK293T

HChrR6 mRNA

Transfection

Extracellular vesicle HER2-binding (EVHB) protein

Incubation

Showed high tumor targeting and protected the function of the prodrug activated mRNA

[110]

Human erythrocyte

RIG-I agonist

Transfection

Anti-human EGFR antibody

OaAEP1 ligase + biotin/avidin reaction

Targeted tumors to activate the innate immune system through the RIG-I receptor (RLR) pathway for anticancer therapy

[99]

M1 macrophage

CD47 and SIRPα antibodies

Azide-modified EBPs bind to dibenzocycloctyne modified antibodies of CD47 and SIRPα via ph-sensitive junctions

Blocked the inhibitory receptor SIRP-α on macrophages and CD47 on tumor cells

[94]

HEK 293F

Microtubule polymerization inhibitor mertansine (DM1) + Verrucarin A (Ver-A)

Incubation + electroporation

anti-SSTR2 and anti-CXCR4 antibodies

DSPE-PEG-NHS linker

Targeted neuroendocrine tumors with chemotherapy drugs

[111]

DC2.4

DSPE-PEG-NHS-aCD3/DSPE-PEG-NHS-aEGFR

Incubation

Promoted the proliferation and activation of T cells and mediated the cross-linking between T cells and B16-OVA cancer cells

[112]

RBC/THP-1

Luciferase mRNA/paclitaxel

REG1 loading reagent + Ultrasonic

EGFR homing peptide

Protein ligases

Low dose targeted delivery of chemotherapy drugs

[100]

RAW264.7 + mouse bone marrow macrophages

Paclitaxel

Ultrasonic

Aminoethylanisamide-polyethylene glycol (AA-PEG)

Ultrasonic with DSPE-PEG-AA

Targeted tumor tissue to improve circulation and the capacity of nanoparticles

HEK293T

Verrucarin A

Incubation

anti-EGFR antibody

DSPE-PEG-NHS linker

Had the ability to cross the blood–brain barrier, the specificity of tumor targeting, and the advantages of providing chemotherapy, gene therapy and other combined therapies

[113]

Photosensitizers

MIA-PaCa-2

Ce6

Ultrasonic

Photodynamic therapy and photoacoustic imaging function

[114]

M1 macrophage

Hydrophilic hypoxia-activated prodrug AQ4N

Incubation

Carbopentoxyphenyl oxalate (CPPO) + chlorin e6 (Ce6)

Incubation

Chemical secondary sources produced active oxygen activated the photosensitizers for photodynamic therapy to promote prodrug conversion

[115]

M1 macrophage

Doxubicin prodrug

Electroporation

Carbopentoxyphenyl oxalate (CPPO) + chlorin e6 (Ce6)

Incubation

Chemical energy generated by CPPO and increased H2O2 can directly activate photosensitizer Ce6 without photoexcitation

[116]

B16F10

Zinc phthalocyanine

Incubation

Photodynamic therapy, combined with cell membrane, can increase the stability of the photosensitizer solubility

[117]

Nucleic acid

J774.A.1

Glutathione-responsive biodegradable silica nanoparticles

Ultrasonic + extrusion

Cholesterol conjugated AS1411

Incubation

Penetrated BBB and targeted cancer cells, alleviated hypoxia within tumors, and improved the efficiency of sonodynamic therapy

[84]

HEK293T

Cas9 RNP

Freeze thawing / Ultrasonic

Tetrahedral DNA nanostructures (TDN) + TLS11a aptamer

Incubation

Tumor specific targeting and delivery of CRISPR/Cas9

[97]

Serum

DOX

Incubation

SPIONs-Tf + chol-miR21i + endosomolytic peptides L17E

Incubation

Improved the escape of endosomes and effectively delivered cargo to tumor cells

[118]

HeLa

AS1411-TMPyP4 + ICG

Incubation

Chol-Sgc8

Incubation

Targeted high expression of protein tyrosine kinase 7 (PTK7) in tumor cells

[119]

Mouse DC cell

Paclitaxel

Ultrasonic

AS1411

Incubate with AS1411-PEG 2000—Chol

Rapid and simple preparation of tumor targeting drugs

[20]

Metal particles

MSCs

SPIONs/ Cell penetrating peptide (CPP) and TNF-α

Incubation/ Transfection

Enhanced tumor targeting and inhibited tumor growth under an external magnetic field

[51]

THP-1

DOX

Electroporation

Polydopamine (PDA) coated magnetic Fe3O4 nanoparticles (Fe3O4@PDA)

Incubation by Biotin-avidin method

Magnetic field guided tumor targeting using chemical, genetic, and photothermal methods resulted in a significant reduction in tumor size

[120]

Neutrophils

DOX

Extrusion with DOX loaded cationic liposome

Superparamagnetic iron oxide nanoparticles (SPIONs)

Incubation

Dual tumor targeting capabilities and loading chemotherapy agents

[121]

Chemotherapeutic drugs

BM-MSCs

Galectin-9 siRNA

Electroporation

Oxaliplatin modified with maleimide (OXA-MAL)

Vortex

Induction of tumor inhibition by macrophage polarization, recruitment of cytotoxic T lymphocytes, and down-regulation of Tregs induced antitumor immunity

[122]

Mannose

DC2.4 + human serum

DOX

Ammonium sulfate gradient method

c(RGDm7)-LS-GE + cationic mannan

Extrusion/ incubation

Saturated macrophage receptors and reduced liver accumulation for subsequent administration

[123]

MSCs

AntagomiR-182 inhibitor

Electroporation

Mannan

Incubation

Targeted macrophages and reversed the immunosuppressive environment

[124]

E. coli BL21 (ΔmsbB)

Redd1 siRNA

Electroporation

DSPE-PEG-CA-PTX和DSPE-PEG-mannose

Incubation

Targeted macrophages and regulated the tumor microenvironment

[125]

Hyaluronic acid

RAW 264.7

DOX

Ultrasonic

Hyaluronic acid

Ultrasonic

Targeting CD44, which is highly expressed on the surface of tumor cells

[126]

Quantum dot

M1 Raw264.7

DOX + hairpin DNA probe

Electroporation

Quantum dot labelling

DNA chain connection

A combination of biotherapeutic and chemotherapy functions and bioimaging capabilities

[127]

DSPE-PEG

Asparagus cochinchinensis

DSPE-PEG

Vortex + ultrasonic

Pegylated nanoparticles can better inhibit tumor growth without significant side effects

[16]