Targeted silencing of Engrailed-1 reprograms profibrotic fibroblast lineage for scarless wound healing

This study develops FibroMC, a nanoscale fibroblast-mimicking siRNA carrier designed to selectively silence Engrailed-1 (En1), a transcription factor that drives profibrotic fibroblast lineage commitment in adult skin. FibroMC is constructed by coating ionizable lipid nanoparticles with fibroblast cell membranes containing integrin β1 and N-cadherin, enabling preferential uptake by Engrailed-1 lineage-positive fibroblasts (EPFs) in vitro and in vivo. Delivery of siEn1 via FibroMC effectively suppresses En1 expression, reduces collagen I deposition, inhibits myofibroblast differentiation, and reverses the profibrotic phenotype of EPFs. In murine wound models, a single topical dose of FibroMC restores epidermal and dermal architecture, regenerates hair follicles and skin appendages, normalizes collagen fiber orientation, and significantly reduces scarring. Mechanical assessments confirm that treated wounds recover near-native skin compliance and elasticity. This work introduces a lineage-targeted RNAi strategy capable of reprogramming pathological fibroblasts to achieve scarless skin regeneration.