Amphotericin B-loaded polyphenolic nanoparticles for synchronous fungal eradication and immunomodulation in treating superficial fungal infections.

Fungal infection represents an escalating global health threat, yet effective treatment remains clinically challenging due to the poor solubility, limited bioavailability, and pronounced cytotoxicity of conventional antifungal agents. To overcome these limitations, a self-assembled nanoparticle (ATE NPs) is developed by integrating amphotericin B (AmB), epigallocatechin gallate (EGCG), and tri(phenylboronic acid)-derived crosslinker pentamethyldiethylenetriamine (T-PBA) for efficient fungal eradication and accelerated tissue repair. Benefiting from the strong affinity of T-PBA towards fungal cell wall polysaccharides, ATE NPs exhibit targeted adhesion and prolonged retention at infected lesions. Within the infection-associated mildly acidic microenvironment, the cleavage of boronate ester bonds triggers the controlled release of AmB, disrupting fungal membranes and eliminating pathogens. Meanwhile, EGCG exerts potent anti-inflammatory and pro-healing effects to promote tissue regeneration. Consequently, ATE NPs exhibit robust mucoadhesion, superior antifungal activity, and remarkable wound-healing capabilities both in vitro and in vivo. In murine models of fungal keratitis and cutaneous mycosis, the multifunctional nanosystem effectively suppresses fungal proliferation, mitigates corneal inflammatory damage and accelerates healing. Furthermore, transcriptomic analysis reveals that ATE NPs induce fungal metabolic dysregulation and oxidative stress while favorably modulating host immune responses. Overall, this work provides a promising, biocompatible nanotherapeutic strategy for the integrated management of severe superficial fungal infections.