5-ALA photodynamic metabolite-powered zero-waste “ferroptosis amplifier” for enhanced hypertrophic scar therapy

Hypertrophic scar (HS) is a somatopsychic disease that significantly affects quality of life. 5-aminolevulinic acid (5-ALA)-mediated photodynamic therapy (PDT) holds promise for HS treatment, while challenges like poor transdermal delivery and rapid metabolism into non_xfffe_photosensitive heme restrict its effectiveness. Inspired by the natural phenomenon of a whale fall nourishing life, this study innovatively repurposes 5-ALA metabolic waste, heme, as a “whale-like” energy source to drive ferroptosis, thus establishing a zero-waste therapy. 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) with pH-responsive programmed drug release. Upon application, 5-ALA is converted into PpIX to initiate PDT. Subsequently, baicalin is released, triggering ferroptosis while also synergizing with the ROS and heme accumulated during PDT to overstimulate the HO-1-heme metabolic axis. This activation releases Fe2+ and CO, further potentiating ferroptosis. Moreover, the enhanced ferroptotic response driven by FAB@MN induces mitophagy, leading to increased Fe²⁺ release from the mitochondria. Unlike conventional PDT only focuses on immediate effects, this approach uses 5-ALA photodynamic waste to fuel a sustained ferroptosis response post-PDT, offering new avenues for HS treatments.