LAUSR

Antimicrobial peptidomimetics (AMPMs) have received widespread attention as potentially powerful weapons against antibiotic resistance. However, AMPMs’ membrane disruption mechanism not only brings resistance‐resistant nature, but also nonspecific binding and disruption toward eukaryotic cell membranes, and consequently, their hemolytic activity is the primary concern on clinical applications. Here, the preparation and screening of an AMPM library is reported, through which a best‐performing hit, PT‐b1, can be obtained. To further improve PT‐b1’s hemocompatibility, a strategy is devised to mask the amphiphilicity of the AMPM using a charge‐free, FDA‐approved amphiphilic polymer, Pluronic F‐127 (PF127). A PF127 solution containing PT‐b1 can form a temperature‐sensitive, absorbable hydrogel at higher concentration, but dissolve and complex with PT‐b1 through hydrophobic interactions at lower concentration or lower temperature. The complexation from PF127 can mask the amphiphilicity of PT‐b1 and render it extremely hemocompatible, yet the reversibility in such nanocomplexation and the existence of a secondary mechanism of action ensure that the AMPM's potency remains unchanged. The in vivo effectiveness of this antimicrobial hydrogel system is demonstrated using a mice wound infection model established with Methicillin‐resistant Staphylococcus aureus, and observations indicate the hydrogel can promote wound healing and suppress bacteria‐caused inflammation even when resistant pathogens are involved.