Table 1.
Reported studies on diabetic wound healing with siRNA targeted against mediators like; Keap1, MMP2, MMP9, TNF alpha, GM3s, PHD2, HIF-1, and IRF5
| Target mRNA | Wound | Study model | Delivery system | Results | Reference |
|---|---|---|---|---|---|
| MMP-2 | 9-mm full-thickness skin wound on the dorsal area of STZ-induced diabetic mice | • in vitro • in vivo Female C57BL/6 mice |
MMP-2 siRNA was chemically tethered to the end of multi-armed PEG and subsequently clustered to submicron particles complexed with linear PEI. MMP-cleavable peptide was used as a linker between PEG and siRNA for stimulus-responsive release of siRNA depending on local MMP concentration. | • downregulated MMP-2 gene expression • long-term MMP-2 gene silencing • Accelerated wound closure |
133 |
| MMP-9 | 10-mm full-thickness skin wound on the dorsal area of STZ-induced diabetic rats | • in vitro • in vivo Sprague-Dawley (SD) rats (6 weeks, male) |
siMMP-9 complexed with Gly-triethylenetetramine (GT) and then loaded into a thermosensitive hydrogel dressing | • downregulated MMP-9 gene expression • biocompatible hydrogel dressing • long-term release of GT/siMMP-9 for up to 7 days • enhanced diabetic wound healing |
127 |
| 10-mm full-thickness skin wound on the dorsal area of STZ-induced diabetic rats | • in vitro • in vivo Sprague-Dawley (SD) rats (5–6 weeks, male) |
MMP-9 siRNA loaded in wound dressing contains hyperbranched cationic polysaccharide (HCP) derivatives. | • downregulated MMP-9 gene expression • biocompatible dressing • enhanced diabetic wound healing |
131 | |
| 10-mm full-thickness skin wound on the dorsal area of STZ-induced diabetic rats | • in vitro • in vivo SD rats (male) |
MMP-9 siRNA encapsulated in a dressing containing bacterial cellulose (BCP)-HCP | • downregulated MMP-9 gene expression • long-term release of MMP-9 siRNA • enhanced diabetic wound healing |
130 | |
| full-thickness skin wound on the dorsal area of STZ-induced diabetic rats | • in vitro • in vivo SD rats |
Star-branched cationic polymer β-CD-(D3)7, which consists of β-cyclodextrin and third-generation poly(amidoamine) (PAMAM) was used as a carrier to take MMP-9 siRNA. | • downregulated MMP-9 gene expression • enhanced diabetic wound healing • decreased infiltration of inflammatory cells around the local wound |
128 | |
| DFU-mimicking conditions | • in vitro | MMP-9 siRNA loaded in collagen/glycosaminoglycan (Col/GAG) scaffolds. | • downregulated MMP-9 gene expression in fibroblast and macrophage cells | 132 | |
| Keap1 | 10-mm full-thickness skin wound on the dorsal area of diabetic mice from The Jackson Laboratory (Bar Harbor, ME). | • in vitro • in vivo male diabetic Lepr db/db mice, aged 12 weeks |
liposome and protein hybrid NP delivery system | • downregulated Keap1 gene expression • increased transfection efficacy Keap1 siRNA • accelerated diabetic tissue regeneration |
134 |
| TNF-α | co-culture model of fibroblast and macrophage cells | • in vitro | LNPs to deliver TNF-α siRNA | • downregulated TNF-α gene expression • decreased production of monocyte chemotactant protein 1 (MCP-1/CCL2) to inhibit the recruitment of additional macrophages to the wound site |
122 |
| 8-mm full-thickness skin wound on the right and left flanks | • in vitro • in vivo genetically diabetic BKS.Cg-Dock7m +/+ Lepr db/J mice |
siTNF-α-loaded LNPs prepared as a potential wound treatment to combat an overzealous immune response and facilitate wound closure in a diabetic mouse model | • downregulated TNF-α gene expression • accelerated diabetic wound healing |
124 | |
| PHD2 | 8 mm full-thickness skin wound on the dorsal area of STZ-induced diabetic rats | • in vitro • in vivo SD rats |
PHD2 siRNA loaded in a porous poly(thioketal-urethane) scaffold | • downregulated PHD2 gene expression • accelerated diabetic wound healing • growth of thicker layer of skin tissue |
135 |
| GM3S | 6-mm full-thickness skin wound on the dorsal area of STZ-induced diabetic mice | • in vitro • in vivo male C57BL/6 mice |
GM3S siRNA loaded on gold NPs | • downregulated GM3S gene expression • accelerated diabetic wound healing • increased keratinocyte migration and proliferation |
136 |
| HIF-1 | • scratch test | • in vitro | HIF-1 siRNA loaded in layer-by-layer (LBL) self-assembled loaded gold NPs with poly L-arginine (AuNP@PLA) in the outer layer | • downregulated HIF-1 gene expression • upregulated pro-angiogenic pathways • accelerated wound healing in an in vitro scratch assay |
137 |
| IRF5 | • scratch test simulated inflammatory condition |
• in vitro | IRF5 siRNA loaded in selenium-based LBL NCs with polyethyleneimine (PEI) as the final polymer layer | • downregulated IRF5 gene expression. • decreased expression level of pro-inflammatory NOS-2 and TNF-α mRNA • increased expression level of the healing mediator Arg-1 • accelerated wound healing in an in vitro scratch assay |
138 |
siRNA, small interfering RNA; STZ, streptozotocin or streptozocin; MMP, matrix metalloproteinase; PEG, polyethylene glycol; Keap1, kelch-like ECH-associated protein 1; TNF-α, tumor necrosis factor alpha; MCP-1, monocyte chemoattractant protein 1; CCL2, chemokine (C-C motif) ligand 2; PHD2, prolyl hydroxylase domain protein 2; GM3S, ganglioside-monosialic acid 3 synthase; HIF-1, hypoxia-inducible factor 1; IRF5, interferon regulatory factor 5.