Table 1.

srNPs activated by internal and/or external stimuli for smart drug release and synergistic cancer immunotherapy

Stimulus	Responsive moiety	Immunomodulator	Tumor type	Ref.
pH	pH‐cleavage: Amide bond pH‐sponge: PDEA	PD‐L1 blockade siRNA and photosensitizer	Melanoma	[ 16 ]
	pH‐cleavage: Amide bond	Isothiocyanate, MEK‐, BRAF‐inhibitor, and anti‐PD‐1	Metastatic melanoma	[ 17 ]
	pH‐protonation: PAA	Au and DOX	Hepatoma	[ 18 ]
	pH‐swelling: Tetraethylenepentamine	RNA interference	Prostatic carcinoma	[ 19 ]
	pH‐responsive size shrinkage: Di‐tert‐butyl dicarbonate	DOX	Breast carcinoma	[ 20 ]
	pH‐responsive shell‐cleavage: Boronate ester bond	Bortezomib	Breast carcinoma	[ 21 ]
GSH	GSH‐cleavage: Disulfide‐bridge	Photosensitizer Ce6, anti‐CTLA‐4 antibody, and Fe3O4	Breast carcinoma	[ 22 ]
	GSH‐cleavage: Tetrasulfide bond	DOX and PD‐L1 antibody	Breast carcinoma	[ 23 ]
	GSH‐cleavage: Disulfide‐bond	Photosensitizer and IDO‐1	Breast carcinoma and colorectal cancer	[ 24 ]
	GSH‐cleavage: Disulfide‐bond	Photosensitizer and IDO inhibitor	Breast carcinoma	[ 25 ]
	Redox‐sensitive linkage: Diselenide bond	PTX	Breast carcinoma	[ 26 ]
	GSH‐cleavage: Disulfide‐bond	Docetaxel and Chondroitin sulfate	Breast carcinoma	[ 27 ]
Enzyme	β‐glucuronidase‐degradation: Glucuronide	Imidazoquinoline TLR7/8 agonist	Raw blue reporter cell line	[ 28 ]
	HAase‐responsive: HA	Cilengitide and TNF‐related apoptosis inducing ligand	Human breast carcinoma	[ 29 ]
	Enzyme‐degradation: Matrix metalloproteinases peptide	TLR7 agonist 1V209 and Cy 5.5 dye	Breast carcinoma	[ 30 ]
	Enzyme responsive: Gly‐phe‐leu‐gly tetrapeptide linker	DOX	Breast carcinoma	[ 31 ]
	Enzyme‐degradation: Matrix metalloproteinases peptide	PD‐L1 inhibitor and DOX	Melanoma	[ 32 ]
	Enzyme‐responsive: Polytyrosine	DOX	Colorectal carcinoma	[ 33 ]
ROS	H2O2‐reaction: MnO2	Gold‐photosensitizer and MnO2	Breast carcinoma	[ 34 ]
	ROS‐trigger: Tellurium nanowire	Bovine serum albumin and dextran	Breast carcinoma	[ 35 ]
	H2O2‐reaction: MnO2	Glycolysis inhibitor and lactate oxidase	Melanoma	[ 36 ]
	H2O2‐reaction: MnO2	Acriflavine	Breast carcinoma	[ 37 ]
	ROS‐cleavage: Thioketal bond	CPT, photosensitizer, and Pt	Colon cancer	[ 38 ]
	ROS‐responsive: Thioether	PTX and Ce6	Breast carcinoma	[ 39 ]
Photo	Photo‐responsive: Photosensitizer PpIX	PpIX and immune checkpoint inhibitor 1MT	Colorectal carcinoma	[ 40 ]
	Photo‐cleavage: O‐nitrobenzyl	DOX	Cervical carcinoma	[ 41 ]
	Photo‐degradation: 9,10‐dialkoxy‐anthracene based precursor	Graphene quantum dot	Breast carcinoma	[ 42 ]
	Photothermal decomposition: PPP	Fe/FeO nanocrystal, ICG, and DOX	Oral epithelial carcinoma	[ 43 ]
	Photo‐responsive: Chloride disulfonic acid	CPT and photosensitizer Al(III) phthalocyanine chloride disulfonic acid	Breast carcinoma	[ 44 ]
US	US‐responsive: Methoxyethyl methacrylate	DOX	Cervical carcinoma	[ 45 ]
	US‐responsive: US contrast agent microbubble	Interfering RNA	Cervical carcinoma	[ 46 ]
	US‐triggered: Ce6 ester	DOX and Ce6	Fibrosarcoma	[ 47 ]
	US‐responsive: Erythrocyte membrane	DOX and hermimether	Hepatoma carcinoma	[ 48 ]
	US‐responsive: 2‐tetrahydropyranyl methacrylate	DOX	Prostatic cancer	[ 49 ]
Magnetic field	Magnetic ferrite	Fe3O4 and MnFe2O4	Breast carcinoma	[ 50 ]
	Mn–Zn ferrite	Mn‐Zn ferrite	Breast carcinoma	[ 51 ]
	Domain iron oxide	Ferrimagnetic vortex and PD‐L1 blockade	Breast carcinoma	[ 52 ]
	Magnetization and superparamagnetism	PD‐1 antibody	Breast carcinoma	[ 53 ]
	Superparamagnetic iron oxide	Fe3O4 and L‐arginine	Breast carcinoma	[ 54 ]
Radiation	Radiation‐cleavage: Diselenide bond	DOX and PD‐L1 checkpoint blockade	Breast carcinoma	[ 55 ]
	Radiation splinter: Au nanocarrier	aPD‐L1	Colorectal carcinoma	[ 56 ]
	Radiation‐diffusion: Adenine‐modified ZnS	DOX	Glioma	[ 57 ]
	Radiation‐responsive mesoporous silica shells of Eu3+‐doped NaGdF4	ICG and s‐nitrosothiol group	Breast carcinoma	[ 58 ]
	Radiation‐responsive splintery snowflake‐like Au	aPD‐L1, Au, and Ag nanocrystal	Pancreatic carcinoma	[ 56 ]
Photo/hypoxia	Light‐triggered/hypoxia‐responsive: 2‐nitroimidazole‐grafted conjugated polymer	DOX	Cervical carcinoma	[ 59 ]
Photo/pH	pH/light responsive: Poly(N‐isopropylacrylamide‐co‐acrylic acid)	DOX and photosensitizer	Cervical carcinoma	[ 60 ]
pH/thermal	pH‐responsive: Acrylamide; thermal‐responsive: Poly(acrylamide‐co‐acrylonitrile)‐PEG	Bovine lactoferricin and HA	Melanoma	[ 61 ]
Photo/pH/hyperthermia	pH‐cleavage: Amide groups; Photo‐cleavage: Ester bond; Photo hyperthermia: Cypate	Cypate and DOX	Breast carcinoma	[ 62 ]
pH/GSH/enzyme	PEG‐peptide‐poly(ω‐pentadecalacto‐ne‐co‐N‐methyldiethyleneamine‐co‐thiodipropionate) block	Ce6 and sorafenib	Lung carcinoma	[ 63 ]

Abbreviations: aPD‐L1, anti‐programmed death ligand 1; Ce6, chlorin e6; HA, hyaluronic acid; ICG, indocyanine green; IDO‐1, indoleamine 2,3‐dioxygenase 1; PAA, polyacrylic acid; PDEA, poly(2‐(diethylamino) ethyl methacrylate; PPP, PLGA−polyethylene glycol−poly(N‐isopropyl acrylamide); TNF, tumor necrosis factor.