Table 1.

Summary of material and carrier choices and release and gene silencing outcomes for local depot-based siRNA delivery.

	Local Delivery Strategy		Intracellular Delivery Strategy	Release Kinetics	siRNA Gene Target/Silencing	Model
Natural Materials	Agarose	Topical matrix	Liposomal complex	Burst over 6 hours	MAPK1, Lamin A/C/>50% at 21 days127	Murine wound model
				Not measured	PHD2/Potent silencing (evaluated by protein expression) at 7, 21 days128
					p53/>75% 2 days after final treatment129
					SMAD3/No silencing shown but functional effect130	Murine skin irradiation model
	Alginate	Hydrogel	PEI, chitosan, or naked110	On the order of days tunable by crosslinking and carrier	deGFP/>90% at 6 days	HEK293s
		Scaffold	Liposomal complex131	On the order of hours tunable by alginate content	Lamin A/C/>85% at 48 hours	Murine, vaginal application
	Dextran	Hydrogel	PEI or naked111	Tunable by dextran content (9–17 days) and carrier	deGFP/>90% at 3, 7, 14 days	HEK293s
	Dextran sulfate/laponite silicate clay, protamine sulfate	LbL film	Calcium phosphate nanoparticles126	Sustained over 7–10 days	GFP/>50% sustained for 7 days	NIH3T3s
	Collagen	Scaffold	PAMAM dendrimers100	Burst in hours	Snail1/>50% at 7 days	NIH3T3s
			Polyplex complex132	Not measured	COL1A1, HtrA1/>50% from 2–10 days	HACs
		Hydrogel	PEI, chitosan, or naked110	Minimal release over 15 days	deGFP/>90% with siRNA released at 6 days	HEK293s
	Chitosan	Hydrogel	Polymer/lipid complexes133	On the order of hours	TG2/>80% at 4 days	Murine tumor model
			Naked134	On the order of days (varies in vitro vs. in vivo)	RANK/>50% at 9 days	RAW264.7s
	Chitosan, HA	LbL film	Chitosan imidazole135	Sustained over 14 days	RhoA/>50% at 48 hours	PC12s
			Chitosan136	Burst in 2 days	Not measured	N/A
			PEI41	Minimal, degradation-based	HCV (antiviral)/>50% at 7 days	Huh7.5s
	Acellular dermal matrix	Coating	Naked137	Burst; 70% in 1 hour	PHD2/>90% at 14 days	Murine cutaneous wound model
Combination	Dextran and PEG-based components	Hydrogel	PLGA microparticles loaded with siRNA-PEI complexes97	Burst in hours	IL-10/>80% at 5 days	Primary mouse APCs
	Alginate, HA, hydroxyethyl cellulose, PCL	Hydrogel	Naked89	Not measured	GFP/>40% at 72 hours	hMSCs
	PAMAM, dextran aldehyde	Hydrogel	PBAE nanoparticles138	30% after 24 hours, then sustained to 90% at 6 days	Luciferase/70% at 6 days	Murine tumor model
Synthetic Materials	PLA, dioxanone PEG,	Hydrogel	Naked139	Not measured	Noggin/>70% at maximum, sustained over 7 days	Murine dorsal muscle pouch
	PCL, ethyl ethylene phosphate	Nano-fibers	Polymer/lipid complex or naked109	Sustained over 10–15 days	GAPDH/>30% at 96 hours	NIH3T3s in vitro
			Polymer/lipid or CPP complex140	On the order of days (carrier-dependent)	COL1A1/maximum >80% in vitro at 3 days, fibrosis reduction in vivo	HDFs in vitro; rat subcutaneous
	PCL	Nano-fibers	Polymer/lipid complex or naked90	Sustained but incomplete release for 28 days	GAPDH/>60% over 30 days	HEK293s in vitro
			Polydopamine141	Burst over 3 days	REST/~30% sustained over 7 days	Mouse NPCs
		Scaffold	Polymer/lipid complex142	Release not measured	BCL2L2, TRIB2/~50% at 72 hours	hMSCs
	PLGA, PLA	Scaffold	Lipidoid complexes143	Release not measured	KDR receptor/~90% at 2, 3 days	hESCs
	Polyurethane	Scaffold	Stimuli-sensitive polymers39, 108	Sustained release for 35 days controllable by fabrication	PPIB, PHD2/>90% at maximum (day 12), potent silencing for 21 days	Murine subcutaneous
	PLGA	Microparticles	PEI	Not measured96	IL-10/~50% at 2 days in vitro, increased survival time in vivo	BMDCs, murine lymphoma model
				Over 30 days dependent on formulation, carrier93	TNFα/20–50% protein-level at 9 days, reduced appetite changes and cytokine production98	Rat joint inflammation model
	PLGA	Nanofibers	Chitosan43	Sustained for 30–35 days	eGFP/~50% at 2 days	H1299s
	PEI and poly(organophos-phazene)	Hydrogel	PEI121	Sustained release for ~24 days in vivo	VEGF/>90% at 2 days	PC-3s
	NIPAAM, double hydroxides	Hydrogel	Naked118	Not measured	GAPDH/>80% at 6 days	Osteoarthritic chondrocytes