Alkyl-chain engineering of berberine-based amphiphilic AIE photosensitizers for dual-model antifungal phototherapy

Superficial mucosal and skin infections caused by Candida albicans remain a clinical burden because current antifungals rarely combine high potency with host safety. Here, we report berberine (BBR)–derived aggregation-induced emission (AIE) photosensitizers for photodynamic therapy (PDT), in which alkyl-chain length is tuned to modulate molecular amphiphilicity, nanoaggregation, and fungal selectivity. A series of cationic AIE derivatives (CABs) was constructed and evaluated for antifungal activity and biocompatibility. Upon 405 nm irradiation, CABs efficiently generated reactive oxygen species through both Type I and Type II photodynamic pathways, including HO• and 1 O₂. In vitro , the medium-chain derivative CAB-8 showed a favorable balance between uptake and cytocompatibility: under 405 nm irradiation, CAB-8 achieved nearly 99.9% fungicidal killing against C. albicans and outperformed fluconazole, while displaying preferential uptake by fungal over mammalian cells, consistent with reduced host phototoxicity. Transcriptomic profiling revealed a dual intrinsic antifungal mechanism under dark conditions, involving concomitant disruption of mitochondrial oxidative phosphorylation and ribosome-dependent protein synthesis. In vivo , CAB-8–mediated PDT enhanced fungal clearance and wound healing in a skin burn infection model and prevented C. albicans colonization in an oral mucosal infection model, without evidence of systemic toxicity. These findings establish alkyl-chain engineering of BBR-based AIE photosensitizers as an effective strategy to improve the efficacy–safety profile of PDT for localized treatment and prevention of superficial C. albicans infections.