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hydroxypropyl methylcellulose. The hydrogel can locally and continuously release the

encapsulated GT/siMMP-9 into the wound tissue through heat-sensitive controlled

release for 7 days, resulting in MMP-9 expression and obviously promoting diabetic
wound healing. Daidi Fan et al. 126 prepared TAsiRNA nanogels for the first time based

on the self-assembled interaction of TA and siRNA. This highly efficient and

biodegradable nanogel was prepared into PHTB (TAsiRNA) hydrogel by crosslinking

with polyvinyl alcohol and human-like collagen. Electrical stimulation improved the in

vivo release of PHTB (TAsiRNA) hydrogels and the endocytosis of the nanogels.

Combination therapy using electrical stimulation and TAsiRNA hydrogels accelerated

diabetic wound healing by lowering ROS and MMP9 levels, promoting macrophage

polarization, collagen production, and angiogenesis. Li Yan et al. 127 developed a

supramolecular peptide hydrogel doped with nanoparticles for local delivery of

siMMP-9. siMMP-9 was encapsulated within nanoparticles fabricated from

amphiphilic cationic lipid-like compounds, subsequently embedded within a

supramolecular peptide hydrogel formed through the self-assembly of amphiphilic

peptides. Not only can the retention time of sirNA-loaded NPs in wound tissue be
significantly prolonged, but also the gradual release of sirNA-loaded NPs from their

porous network can improve the siRNA uptake rate of keratinocytes, thereby achieving

efficient MMP9 silencing and significantly improving diabetic wound healing. Zecong

Xiao et al. 128 highlighted the critical role of m6A methylation in diabetic wound healing,

clarifying the mechanism by which m6A modification regulates MMP9 expression

during this process. By combining enhanced mRNA m6A modification with ROS

scavenging strategy, we utilized a FTO inhibitor loaded nanocolloidal hydrogel in a

diabetic model, which showed excellent wound healing effect.

Furthermore, diabetic wounds represented a complex chronic pathological

condition resulting from the interplay of multiple systemic and local factors, where in

any single factor may exacerbate the wound during the healing process. Consequently,

the development of multifunctional hydrogels capable of simultaneously addressing

infection, inflammation, and impaired angiogenesis was crucial for clinical efficacy 129 .

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