A miRNA Nanoprodrug Hydrogel for Multistage Regulation of Burn Wound Repair

ABSTRACT Burn wound repair requires not only rapid wound closure but also coordinated regulation of the evolving pathological processes across distinct healing stages to minimize scar formation. However, many existing wound dressings address only isolated aspects of healing and are often limited by burst release, short local retention, and insufficient intracellular delivery. Here, we report ATMP@Gel, a GelMA hydrogel incorporating an activatable tetrahedral miR‐146a‐5p nanoprodrug (ATMP), for multistage regulation of burn wound repair. The tetrahedral nanoframework improves miRNA stability and cellular uptake, while the hydrogel matrix prolongs local delivery; RNase H‐responsive activation further contributes to increasing the functionally available intracellular pool of miR‐146a‐5p. ATMP@Gel attenuates excessive inflammation and oxidative stress during early repair, shifts the macrophage marker profile toward a reparative state, and suppresses fibroblast overactivation and profibrotic remodeling at later stages of healing. In a murine full‐thickness burn model, ATMP@Gel accelerates wound closure and promotes angiogenesis, re‐epithelialization, restoration of skin appendage structures, and more normal‐like collagen architecture, while reducing residual scar area and scar‐associated fibrosis. Together, these findings demonstrate a miRNA nanoprodrug hydrogel strategy that integrates sustained local delivery with responsive intracellular regulation to coordinate multiple pathological processes throughout burn wound healing.