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

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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 dissolv

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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