Overcoming Antifungal Resistance: A Histatin 5-Gated Nanodevice for On-Demand Surfactant Delivery against C. albicans Infections.

The escalating incidence of fungal infections, coupled with the emergence of antifungal resistance, represents a formidable global public health challenge. Candida albicans is a common opportunistic fungus that causes life-threatening, widespread candidiasis, especially in immunocompromised patients. Conventional antifungals, including azoles, echinocandins, and polyenes, have some drawbacks, such as host toxicity and the rapid appearance of resistant fungal strains. To overcome these limitations, we engineered a stimuli-responsive gated antimicrobial nanoparticle using mesoporous silica nanoparticles, functionalized with the antimicrobial peptide histatin 5 (Hst5) and loaded with the surfactant (3-(methyl)-1-tetradecylimidazolium) [C14MIM]+. The nanoparticles exhibit potent antimicrobial activity against C. albicans, with minimum inhibitory concentration values comparable to current clinical antifungals. Crucially, the nanodevice exhibits a dual mechanism of action, causing membrane disruption and inducing reactive oxygen species generation, which effectively hinders the development of resistance. Furthermore, the nanoparticles display strong synergistic interactions with conventional antifungals, significantly enhancing their efficacy. In addition to its planktonic activity, the system effectively inhibits biofilm formation and demonstrates high biocompatibility with human dermal cell lines. Based on these results, the nanodevice is successfully incorporated into a wound dressing matrix, demonstrating its promising translational potential for the topical treatment of cutaneous candidiasis.