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) (PArg 20 ) with a phage-like action process was synthesized, exhibiting superior antifungal activity and favorable biocompatibility. Emulating the three-step infection process of bacteriophages, PArg 20 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, PArg 20 triggers a programmed cascade of intracellular disruptions, including mitochondrial dysfunction, oxidative stress, and nuclear rupture. Compared with the clinically used antifungal drug, PArg 20 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, PArg 20 significantly reduces fungal burden and inflammation. Overall, the phage-like action process exhibited by PArg 20 provides an antifungal approach that may help combat fungal infections while limiting the emergence of resistance.