Caged-hypocrellin-mediated antimicrobial photodynamic therapy as a dual-action strategy for fungal clearance and immune response regulation in drug-resistant Candida auris wound infections.

Abstract

Multidrug-resistant Candida auris is designated by the World Health Organization as a critical priority pathogen. Its bloodstream infections have ∼40% mortality and predominant cutaneous origin, necessitating early local control. With limited treatment options, new antifungal strategies are urgently needed. Antimicrobial photodynamic therapy (aPDT) has shown promise for superficial infections, although its immune-modulating mechanisms remain unclear. To assess antifungal and immunomodulatory effects of aPDT on multidrug-resistant C. auris skin wound infection. A murine wound model using C. auris CBS14918 was treated with COP1T-HA-based aPDT. Fungal burden, wound healing, immune profiles, and transcriptomic responses were evaluated. COP1T-only and dark groups were excluded from immunological analyses because prior validation revealed a lack of efficacy. aPDT significantly reduced fungal burden and accelerated wound healing. It enhanced local infiltration of myeloid cells, B cells, γδ T cells, and type 2 innate lymphoid cells, while controlling systemic inflammation. Transcriptomic data confirmed a balanced cytokine profile supporting fungal clearance and tissue repair. The study used only animal models, as proof-of-concept therapies cannot be ethically tested in humans. aPDT eradicates drug-resistant C. auris and enhances wound healing via immune modulation. These effects support its potential as a preclinical strategy when human studies are ethically prohibited.