Spatiotemporally Controlled Restoration of GAS6 Signaling via mRNA Therapy Promotes Scarless Healing in Preclinical Models
Deep cutaneous injuries in adult mammals often lead to fibrotic scarring, a process exacerbated by inflammatory fibroblasts that amplify immune recruitment. Early modulation of immune–fibroblast crosstalk represents a promising therapeutic strategy. Here we show that GAS6 is a key regulator of this interaction and can be therapeutically targeted using a spatiotemporally controlled lipid nanoparticle (LNP)–mRNA hydrogel platform. We engineer LNP-GAS6 mRNA to enhance macrophage efferocytosis and suppress inflammatory fibroblasts, then encapsulate it in a thermosensitive hydrogel for localized delivery. In murine, rabbit ear, and Bama minipig wound models, this treatment significantly accelerated wound closure and reduced fibrotic scarring. These results demonstrate that restoring GAS6 signaling via mRNA-based delivery promotes scarless healing and offers an effective therapeutic approach for fibrotic skin disorders. Overall design: Male C57BL/6 mice (6-8 weeks) underwent dorsal full-thickness 6-mm circular excisions under intraperitoneal injection anesthesia, stabilized with silicone rings and 3M Tegaderm film (inhibiting wound contraction). Treatments included hydrogel + LNP and hydrogel + GAS6 mRNA-LNP. Peri-wound tissues were harvested at day 3.