Table 2.

Smart Features of St-Mc-DDS

St Type	Mc-Targeted Material	Drug	Preparation	Response Mechanism	Function	Ref.
Endogenous stimuli-responsive En-St-Mc-DDS
pH	PEG-Schiff base-cholesterol; Dioleoylphosphoethanolamine	TPP-PTX	Liposome	Schiff-based bond hydrolyzes at pH 6; DOPE merge with tumor lysosome membrane at pH 5.0	Remove PEG shell; Release drug into cytoplasm; Ingest drug in Mc	[42]
	CTPP-glucolipid conjugates	Celastrol	Micelle	Celastrol is highly soluble at Mc pH 8.0	Fast drug release at Mc; Low leakage in cytoplasm and lysosome.	[43]
	HER-2 peptide-PEG-Schiff base-cholesterol; Dequalinium chloride vesicle	DOX	Liposome	Schiff-base bond hydrolyzes at pH 5.0–6.8	Remove PEG-shell; Enhance drug release; Lower non-specific toxicity	[36]
	PEG-AIE-TPP	AIE	Micelle	Hydrazone bonds of the micelles are ruptured at pH 5.3 or 6.5	Remove PEG chain; Reduce the side effects; Increase bioavailability	[44]
	N-(2-hydroxypropyl) methacrylamide polymer	MSN-DTX	Nanohybrid	Amide bond hydrolyzed at acidic pH; Nanohybrid dismissed in the endo/lysosomes at acidic pH	Partial presentation of MSN core and positive charge repulsion contribute to cellular internalization; Positive core leakage help endo/lysosome flee and Mc-targeting	[45]
	Phenylboronic acid-PEG	TPP-Que	Nanoparticle	Coordination bond disrupt at acidic pH	De-PEGylation; Facilitate cellular ingestion and arrangement	[46]
	DSPE-KLA-DMA	PTX	Liposome	Amide bond break down at pH 6.8	Reverse charge from negative to positive; Promote cellular internalization	[47]
	PDPA/TPGS	DOX	Micelle	Diisopropyl-substituted tertiary amino groups are protonated at pH 5.5	Dissociate micelle; Release drug; TPGS synergistically enhance DOX effect by accumulating at Mc and lowering transmembrane potential.	[48]
	1,5-dioctadecyl-L-glutamyl 2-histidyl-hexahydrobenzoic acid [HHG2C(18)]	–	Liposome	Reverse charge (negative to positive) at pH 6.5; Hydrolyze hexahydrobenzoic amide at pH 4.5~5.5 in endolysosome	Increase cellular uptake; Uptaken at Mc by electrostatic interaction	[49]
Redox	TPP-OHA-S-S-CCM	CCM	Micelle	Disulfide bonds break at a high GSH level (2~10 mM)	Release drug rapidly	[50]
	PLGA/C18-PEG2000-TPP/DLPE-S-S-mPEG4000	PTX	Nanoparticle	The disulfide bonds break at a high GSH level (2~10 mM)	Detach PEG4000; Recover surface charges; Localize at Mc	[51]
Enzyme	HA/PEG	Berberine derivative	Nanodrug	Degrade HA by hyaluronidase	Expose positive charge contributes to cellular ingestion, lysosome flee and Mc location	[19]
	Non-isocyanate polyurethane-TPP	DOX	Nanocapsule	Ester linkages rupture by esterase.	Degrade polymer backbone; Release drugs site-specifically; Apply organelle-specific imaging	[52]
	Phe-Phe-Tyr-Lys (FFYK)	TPP-peptide	Nanoscale assemblies	Dephosphorylation catalyzed by ectophosphatases	Oligomers self-assemble to form nanoassemblies on cancer cell surface	[53]
	DNA-condensing/cell-penetrating/endosome-disruptive and mitochondria-targeting sequences	pDNA	Peptide/DNA complexes	Lysine-specific interaction	Self-organization of peptide and DNA; Structural rearrangement of complex	[37]
Exogenous stimuli-responsive Ex-St-Mc-DDS
Light	IR780	IR780	Perfluorooctyl bromide nanoliposome	Convert energy from laser into heat through a plasmonic PTT effect; Convert oxygen into toxic ROS under irradiation at 808 nm	Mc-targeted PTT; PTT/PDT effects; Multiply imaging monitoring	[54]
	Fe3O4	Iridium	Nanozyme	Convert energy from laser to heat through a PTT effect; Convert H2O2 to toxic hydroxyl group	Induce Mc-targeted PTT; Accelerate H2O2 catalysis	[55]
	IR-780/DPPC/DSPC/DSPE-PEG2K-TPP	IR-780; Lonidamine	Liposome	Irradiate at 808 nm triggers IR-780 to elevate temperature to further release lonidamine from liposomes; IR-780 release ROS	Achieve Mc-targeting combinative therapy of thermosensitive chemo-, PDT/PTT	[56]
	mPEG-CHO-PAIE-TPP	AIE	Nanoparticle	Benzoic imine bond cleaves in acidic tumor environment; AIE is photoactivated by up-converted energy upon irradiation at 980 nm	Remove PEG shell; Generate ROS in Mc and induce cell apoptosis	[57]
	AuNS-KLA-TPP/HA	DOX	Nanoparticle	Convert energy from laser into heat through a PTT effect of gold nanostars	Achieve Mc-targeted PTT	[58]
	TPP/Ce6/PEG-/FA-PEG-Pt@Au	Pt; Au	Nanoparticle	Convert energy from laser (808 nm) into heat through a PTT effect of Pt/Au nanoparticles	Achieve Mc-targeted multifunctional PDT/PTT strategies	[59]
	Au-dcHSA-PEO-TAT-TPP	Au	Nanoparticle	Convert energy from laser (808 nm) into heat through a PTT effect of gold nanoparticles	Probe cellular processes (Mc dynamics and cellular vitality)	[60–63]
	PPa-NGO-mAb	PPa	Nanodrug	Convert oxygen into toxic ROS under irradiation at 633 nm	Enhance Mc-mediated apoptosis of PDT	[64]
	Yb/Tm/TiO2	Yb/Tm/TiO2	Nanoparticle	Transform NIR light to UV emission to favor TiO2 absorption; Generate intracellular ROS under irradiation	Achieve photosensitivity to NIR and produce PDT	[65]
	TPP-coumarin- Fe3O4	Fe3O4	Nanoparticle	Convert energy from laser (740 nm) into heat through a PTT effect	Achieve Mc-targeted PTT	[66]
	Cyt C aptamer-mesoporous silica-Au	Au	Nanorod	Convert energy from laser (808 nm) into heat through a PTT effect	Integrate targeting, light-triggered release, and chemo-PTT	[67]
	SWNT-PEG	SWNT	Nanotube	Convert energy from laser (980 nm) into heat through a PTT effect	Achieve Mc-targeted PTT; Minimize adverse side effects	[68]
Magnetic field	PK-CP-SPION	DNA	SPION	Magnetism-guided gene delivery	Magnetism-guided deliver gene and achieve Mc-targeting therapy; Enhance therapeutic effect	[69]
	Fe3O4@mSiO2-TPP/CDs	Fe3O4	Nanoparticle	Magnetism-guided cellular ingestion	Integrate long time imaging, Mc-targeting, and magnetism-guided cellular uptake	[70]
	AMB-1-Cyt c aptamer	AMB-1	Bacterial magnetic nanoparticle	Magnetism-enhanced cellular uptake	Selectively locate at Mc cytochrome C; Remotely control over subcellular elements	[71]
Multi-responsive St-Mc-DDS
pH/light	Catalase@SiO2/Ce6-CTPP/DPEG	Catalase; Ce6	Nanoparticle	Reverse surface charge (negative to slight positive) at pH 6.8; Decompose tumor endogenous H2O2 by catalase; Convert oxygen into toxic ROS under irradiation at 660 nm	Enhance cell ingestion and tumor retention; Produce O2 to enhance PDT efficacy;	[20]
	Fe3O4@DMSA/DOX	DOX; Fe3O4	Nanoparticle	Release DOX by pH and NIR-light triggers; Convert energy from laser (808 nm) into heat through a plasmonic PTT effect	Achieve chem-PTT; Kill cell death by disrupting Mc through ROS generation	[72]
Redox/light/magnetic field	Fe3O4/TPP-PDA-s-s-mPEG	DOX; Fe3O4	Nanoparticle	Disulfide bond linker is cleaved at high reduced glutathione; Convert energy from laser (808 nm) into heat through a plasmonic PTT; Disrupt π–π stacking between aromatic regions of PDA and DOX	Detach mPEG shell from nanoparticles to produce TPP; Release DOX rapidly; Achieve Mc-targeted chem-PTT	[73]
Magnetic field/light	Fe3O4@PDA@mSiO2-TPP/-PEG	Fe3O4	Nanoparticle	Hyperthermia and toxic ROS are induced under a single irradiation at 670 nm	Achieve Mc-targeted chem-PTT; NIR fluorescence imaging and magnetic resonance imaging	[74]
pH/redox/temperature	MBA-PDA-PEG-PNiPMA	Pc 4	Nanogel	Rapid intracellularly self-expand at body temperature and reduce environment; Release Pc 4 at suitable pH and redox potential; Convert oxygen into toxic ROS under irradiation at 670 nm	Control drug release at targeted sites and enhance therapeutic effect	[75]
Redox/light	PPA	TPP-PPA	Micelle	Produce singlet oxygen by TPP-PPA/PPA upon laser irradiation	Disassemble micelle and release cargo rapidly	[76,77]
Redox/enzyme	Glucose-polyethylene glycol (PEG)-peptide-TPP-polyamidoamine (PAMAM)-PTX	PTX	Conjugate	Detach MMP2-sensitive PEG layer from inner PAMAM and release PTX due to GSH-sensitivity	Increase tumor cellular ingestion; Acquire glucose-mediated tumor targeting; Achieve Mc location	[78]

Note: Mc-targeting ligand is written in bold face.

Abbreviation: PSC, PEG-Schiff base-cholesterol.