Cu ²⁺ ‐Guided Adaptive Nano‐Self‐Assembly Drives Infection‐Responsive Antimicrobial Therapy

ABSTRACT Short antimicrobial peptides (AMPs) are promising alternatives to conventional antibiotics; however, their clinical translation is often limited by rapid systemic diffusion, non‐specific distribution, and insufficient on‐demand activation within infectious microenvironments. Here, a Cu 2+ ‐guided, infection‐responsive antimicrobial platform is reported based on a tyrosine (Y)‐modified, tryptophan (W)‐rich short‐AMP, (RWW)2Y7 (RWY). RWY was integrated into a mesoporous polydopamine (MPDA) carrier via dynamic metal‐phenol coordination, forming MPDA‐Cu 2+ ‐PEG@RWY (MCPR), which enables controlled peptide release under weakly acidic infection conditions (pH 5.5). Upon release, RWY interacts with co‐released Cu 2+ through cation‐π interactions, generating a pre‐aggregated state that undergoes bacteria‐responsive in situ self‐assembly upon exposure to lipopolysaccharide (LPS) or lipoteichoic acid (LTA). This adaptive nanoassembly markedly enhances antibacterial activity by inducing membrane disruption and depolarization, intracellular content leakage, metabolic collapse, ATP depletion, and excessive reactive oxygen species (ROS) accumulation. Transcriptomic analysis further reveals broad suppression of ribosome biogenesis, energy metabolism, membrane transport, and extracellular polymeric substance (EPS)‐associated pathways, thereby dismantling biofilm‐related defense barriers. These coordinated effects translate into robust in vivo efficacy in methicillin‐resistant Staphylococcus aureus (MRSA)‐induced skin infection and peritonitis models, alongside a favorable biosafety profile. Overall, this work establishes a programmable, bacteria‐triggered self‐assembly strategy that advances short‐AMPs toward precision anti‐infective functional materials.