Augmenting the Precise Targeting of Antimicrobial Peptides (AMPs) and AMP‐Based Drug Delivery via Affinity‐Filtering Strategy

Abstract Antimicrobial peptides (AMPs) have aroused extensive attention due to their low incidences of resistance, yet their clinical transformation is thwarted by inferior selectivity and metabolic stability concerns, manifesting as rapid degradation, off‐target, and non‐selective toxicity. Here, a captivating affinity‐filtering strategy is proposed as a feasible solution for such challenges. Specifically, based on the selective affinity of AMPs toward distinct phospholipids, the membrane of host cells (e.g., erythrocytes) is pre‐bound to AMPs as the “filter,” which could screen out off‐target substances with non‐specific affinity while maintaining effective interaction with high‐affinity pathogens through competitive binding, realizing precise targeting, and enhanced stability. The practicability of the affinity‐filtering strategy has been demonstrated both in vitro and in vivo, through systematic studies on various AMPs and AMPs‐modified delivery systems with multiple fungal infection models ( Candida albicans and Cryptococcus neoformans ), which pose severe threats to human health worldwide yet are often neglected. AMP‐modified nanoparticles with affinity filtering exhibit reduced off‐target toxicity, sufficient binding with target pathogen, as well as a substantially elevated 21‐day survival rate from 30% (conventional drug‐loaded nanoparticles) to 70%. In summary, this strategy may provide inspiration for overcoming off‐target effects in drug targeting and further promote the clinical application of AMPs.