Photodynamic metabolite-powered zero-waste “ferroptosis amplifier” for enhanced hypertrophic scar therapy

Abstract

Hypertrophic scar (HS) is a somatopsychic disease that significantly affects quality of life. 5-aminolevulinic acid (5-ALA)-mediated photodynamic therapy (PDT) shows promise for HS treatment, while challenges like poor transdermal delivery and the accumulation of photodynamic by-products restrict its effectiveness. Inspired by the natural phenomenon that a whale fall brings life to thousands, this study proposes a zero-waste strategy by leveraging the photodynamic metabolite heme to establish a “ferroptosis amplifier”, which allows these metabolic wastes to be transformed into new sources of energy, thereby amplifying ferroptosis response following PDT. This is achieved by encapsulating 5-ALA and baicalin within human H-ferritin (HFn), subsequently incorporated into polyvinylpyrrolidone (PVP) microneedles (FAB@MN). The FAB@MN exhibits excellent targeting towards hypertrophic scar fibroblasts (HSFs) and pH-responsive programmed drug release. The treatment begins with the release of 5-ALA, which is converted into PpIX to activate PDT. Baicalin is then released, which directly triggers ferroptosis while also facilitating the breakdown of photodynamic waste heme into Fe2+ and CO, thereby amplifying ferroptosis. Unlike conventional PDT only focuses on immediate effects, this approach uses photodynamic waste to fuel a sustained ferroptosis response after PDT, offering a new path for treatment.