The poly-(HA-GMA) hydrogel carrying AAV8-sTβRII alleviates scar formation in mice skin wound healing by inhibiting fibrosis.

Effective scar control requires selectively suppressing late-stage fibrosis without compromising early wound closure. We developed a localized, time-staged delivery system. A poly-(HA-GMA) hydrogel serves as a short-term depot, loaded with AAV8-sTβRII and applied directly along the wound margin. Materials characterization showed a water-rich porous network that rapidly imbibes and releases vector primarily by diffusion. In vivo, the hydrogel naturally degrades in ~3 days, enabling local enrichment in early healing without excessive retention. In a mouse full-thickness skin-wound model, this approach achieved efficient transduction of the cutaneous and fascial layers while markedly reducing hepatic exposure. From postoperative day 6 onward it accelerated closure and produced a thinner dermis, more orderly collagen organization, and a lower collagen area fraction. Mechanistically, Flag-sTβRII was detected within scar tissue. Phospho-Smad2/3 and α-SMA were reduced, whereas total Smad2/3 was largely unchanged, indicating that inhibition occurs at the activation step of the TGF-β/Smad pathway. Moreover, adding exogenous TGF-β1 reversed the macroscopic and histological benefits, strengthening the evidence for pathway specificity. Compared with direct intradermal injection, hydrogel delivery simultaneously increased local expression and limited systemic spillover. Using the AAV8 capsid provided the most favorable balance-high in skin, low in liver. Safety readouts-including body weight, serum transaminases, and histology of major organs-showed no abnormalities. To our knowledge, the "HA-GMA × AAV8-sTβRII" strategy precisely aligns pathway antagonism with the escalation phase of fibrosis, yielding improvements from molecular and cellular phenotypes to tissue remodeling and healing. It offers a generalizable, materials-biology integrated platform for anti-fibrotic gene therapy at the wound edge.