Rational design of FAP-targeted sEVs delivered by microneedles for precision treatment of hypertrophic scars via ferroptosis in hypertrophic scar fibroblasts

Hypertrophic scars (HS) lack cell-specific therapies because pathogenic hypertrophic scar fibroblasts (HSFs) are hard to inactivate without damaging human dermal fibroblasts (HDFs). Ferroptosis has emerged as a potential antifibrotic vulnerability of activated fibroblasts, yet its translational use is constrained by off-target toxicity of small-molecule inducers. Here, we report a targeted delivery strategy based on small extracellular vesicles (sEVs) surface-decorated with a fibroblast activation protein (FAP) ligand to preferentially deliver a widely used ferroptosis inducer erastin to HSFs. We confirmed that FAP is upregulated in HSFs and HS tissue, and engineered adipose-derived mesenchymal stem cell (ADSC)-derived sEVs loaded with erastin and covalently conjugated with the FAP ligand UAMC1110 (sEVs ErF ) via EDC/NHS chemistry. sEVs ErF retained typical nanoscale characteristics and EV marker profiles and showed preferential uptake by HSFs over HDFs in vitro , which was validated by competitive blocking and FAP knockdown experiments. Functionally, sEVs ErF suppressed HSF proliferation and migration and reduced α-SMA, COL I, and COL III expression, accompanied by ferroptosis-associated signatures including lipid peroxidation, glutathione depletion, labile Fe 2+ accumulation, and mitochondrial dysfunction. For localized dermal delivery, sEVs ErF were incorporated into dissolvable microneedle patches (DMNPs) with GelMA tips and a PVA backing. In a rabbit ear HS model, sEVs ErF -DMNPs reduced scar thickness and collagen deposition and modulated ferroptosis- and fibrosis-related readouts in scar tissues. Both in vitro and in vivo rescue experiments using the ferroptosis inhibitor Ferrostatin-1 confirmed that these effects were specifically mediated by ferroptosis. Collectively, these results support FAP as an actionable targeting handle for preferential delivery to scar fibroblasts and suggest that ferroptosis-associated inactivation of HSFs can be leveraged through a microneedle-enabled, locally retained sEV formulation.