Self‐Assembled Poly(sarcosine) Functionalized Host Defense Peptide‐Mimicking Poly‐β‐Peptides for Combating Drug‐Resistant Fungal Infection

Abstract The scarcity of clinically available antifungal drugs, coupled with frequent side effects and the accelerating emergence of fungal drug resistance, underscores the pressing demand for novel antifungal drugs. Host defense peptide (HDP) assemblies are one of the ideal alternatives to antifungal drugs due to the distinctive advantages of nanostructures, but still face challenges in terms of in vivo stability, biosafety, and facile synthesis. Poly‐β‐peptides are a class of polypeptide mimics that possess excellent biocompatibility and resistance to proteolysis, however, their antimicrobial assemblies have yet to be explored. Herein, the advantages of poly‐β‐peptide and poly(sarcosine) are integrated to design self‐assembled poly(sarcosine) functionalized HDP mimics, while establishing a one‐pot, open‐vessel synthesis method for block‐like poly‐β‐peptide. The synthesized multifunctional poly‐β‐peptide assemblies exhibit potent and highly selective antifungal activity against drug‐resistant fungi with excellent biosafety, effectively eradicate mature biofilms, and demonstrate potent in vivo antifungal efficacy. Notably, fungi are insusceptible to acquire resistance against the assemblies owing to the antifungal mechanisms associated with organelle destruction and reactive oxygen species. These results demonstrate the potential of the strategy in developing self‐assembled HDP mimics and combating drug‐resistant fungal infections.