Membrane-Targeting Poly(Amino Acids) with a Phage-Like Action Process for Antifungal Therapy

Invasive fungal infections and the rising prevalence of drug resistance highlight the urgent need for alternative antifungal strategies. In this study, a guanidine-functionalized poly(amino acid) (PArg₂₀) with a phage-like action process was synthesized, exhibiting superior antifungal activity and favorable biocompatibility. Emulating the three-step infection process of bacteriophages, PArg₂₀ exhibits a phage-like "adsorption-penetration-disruption" action process. Initially, electrostatic interactions contribute to membrane adsorption for targeting, followed by membrane penetration driven by translocation ability and local membrane perturbation. Once internalized, PArg₂₀ triggers a programmed cascade of intracellular disruptions, including mitochondrial dysfunction, oxidative stress, and nuclear rupture. Compared with the clinically used antifungal drug, PArg₂₀ reduced the time required for fungal eradication from over 2 h to just 10 min and showed no significant tendency toward resistance after 15 consecutive passages. In murine corneal and systemic fungal infection models, PArg₂₀ significantly reduces fungal burden and inflammation. Overall, the phage-like action process exhibited by PArg₂₀ provides an antifungal approach that may help combat fungal infections while limiting the emergence of resistance.