Organic photosensitizers for antifungal therapy: structural diversity and emerging applications.

Abstract

Drug-resistant and biofilm-associated fungal infections remain difficult to treat with conventional antifungals. Antimicrobial photodynamic therapy (aPDT) uses light-activated organic photosensitizers to generate multi-target oxidative damage with spatiotemporal control. To establish how molecular design governs antifungal performance, this review critically compares natural product-derived photosensitizers, cyanine dyes, porphyrinoids, BODIPYs, aggregation-induced emission luminogens, and emerging molecular platforms for antifungal aPDT. We examine how charge, hydrophobicity, heavy-atom substitution, donor-acceptor architecture, aggregation, formulation, and subcellular targeting influence fungal selectivity, Type I and Type II photochemistry, biofilm access, imaging, and preclinical efficacy. Cross-class analysis further identifies major barriers to translation, including host-cell phototoxicity, oxygen-limited biofilms, restricted optical access, inconsistent dosimetry, the predominance of Candida albicans as an experimental model, and limited pharmacokinetic and long-term safety data. Future progress will require red- and near-infrared-responsive photosensitizers, infection-site-adapted delivery and illumination, direct validation under defined oxygen-limited conditions, standardized photochemical and dosimetric reporting, and broader evaluation in mature biofilms and clinically diverse fungal pathogens.