Table 1 Representative internal-stimuli responsive nanoformulations for CRISPR-Cas9 delivery

pH

Cationic block copolymer P(Asp-AED-ICA)–PEG, with imidazole residues and disulfide bonds

RNP

EGFP;

mCherry

In vitro (mCherry-expressing HEK 293 human embryonic kidney cells)

-

[131]

pH

Zeolitic imidazole frameworks (ZIFs)-8 co-encapsulating Cas9 protein and sgRNA

RNP

EGFP

In vitro (Chinese hamster ovary (CHO) cells)

-

[98]

pH

ZIF-8 encapsulating plasmid

Plasmid

EGFP-tagged paxillin

In vitro (U2OS human bone osteosarcoma epithelial cells)

-

[99]

pH

AuNP-based CRISPR nanoformulation

RNP

Chemokine receptor 5 (CCR5);

gamma (γ)-globin

In vivo (NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/Szj (Il2r gamma^−/−) mice)

Intrahepatic injection of CD34⁺ cells treated by AuNP/CRISPR

[106]

pH

Cas12a/crRNA RNP-loaded DNA nanoclew with a coating of PEI and Gal-PEI-DM layers

RNP

EGFP;

PCSK9

In vivo (C57BL/6 mice)

Intravenous injection

[108]

pH

pH-responsive mPEG-PC7A amphiphilic copolymer self-assembly

RNP

GFP;

BFP;

tdTomato;

dystrophin

In vivo (B6.Cg-Gt(ROSA)26Sor^{tm14(CAG−tdTomato)Hze}/J mice and C57BL/10ScSn-Dmd^mdx/J)

Intravenous injection; intramuscular injection; and intratracheal injection

[110]

pH

DNA-conjugated gold nanoparticles complexed with PAsp(DET)

RNP

BFP;

GFP;

CXCR4;

tdTomato;

dystrophin

In vivo (Ai9 mice, C57BL/10ScSn (wild-type) mice, and C57BL/10ScSn-Dmdmdx/J (mdx) mice)

Intramuscular injection

[111]

pH

NP with a cationic PEI–PLGA core and a PEG corona

Plasmid

GFP;

cyclin-dependent kinase 5 (Cdk5)

In vivo (B16F10 melanoma in C57BL/6 mice; CT26 colorectal carcinoma in BALB/c mice)

Intravenous injection

[115]

pH

Fluorinated acid-labile branched hydroxyl-rich polycation

Plasmid

Renilla luciferase; EGFP;

survivin

In vivo (A549 epithelial carcinoma in BALB/c mice)

Intravenous injection

[116]

GSH

Nanocapsule with a GSH-cleavable covalently crosslinked polymer coating

RNP

mCherry;

tdTomato;

a stop cassette before tdTomato (Ai14)

In vivo (Ai14 mice)

Subretinal injection;

intramuscular injection

[127]

GSH

Silica NPs integrated with disulfide bond-containing crosslinker

mRNA, or RNP

GFP;

BFP;

RFP;

tdTomato

In vivo (Ai14 mice)

Subretinal injection; intravenous injection

[128]

GSH

Leading lipid BAMEA-O16B

mRNA/sgRNA

GFP;

RFP;

PCSK9

In vivo (C57BL/6 mice)

Intravenous injection

[129]

ROS

Cationic poly(β-amino ester) with macrophage membrane coating and precursory molecule BAM-TK-TMP anchoring

Plasmid

EGFP;

prolyl hydroxylase domain 2 (PHD2)

In vivo (BALB/c mice with colitis)

Intravenous injection

[143]

MMP/HAase/ROS

Programmable unlocking nano-matryoshka-CRISPR system with ROS-sensitive PEI derivative core and coated RGD-MMP substrate, hyaluronic acid, and PEG

Plasmid

EGFP;

PD-L1;

PTPN2

In vivo (B16F10 melanoma in C57BL/6 mice, A375 melanoma in BALB/c nude mice)

Intravenous injection

[154]

Ribonuclease H

Gold nanorod modified with nuclear targeting peptide and cell-type-specific aptamer

RNP

EGFP;

PLK1

In vitro (MCF-7 breast cancer cells)

-

[162]

ATP

ZIF-90/protein nanoparticles by self-assembly of imidazole-2-carboxaldehyde and Zn²⁺ with protein

RNP

GFP

In vitro (HeLa cervical carcinoma cells)

-

[166]

Hypoxia

Gold nanorods conjugated with azobenzene-4,4′-dicarboxylic acid linker

RNP

EGFP;

Hsp90α

In vivo (A549 epithelial carcinoma in nude mice)

Intravenous injection

[169]

MicroRNA

DNA nanoflowers with multiple replicates of MUC1 aptamers and miR-21 binding sequences

RNP

EGFP

In vivo (HeLa cervical carcinoma in BALB/c mice)

Intratumoral injection

[176]