Antimicrobial/Anti-Inflammatory Peptidomimetic-Polyphenol Co-Assemblies with pH-Triggered Activation for <i>S. aureus</i> Abscess Therapy

The treatment of Staphylococcus aureus subcutaneous abscesses is hindered by the protective abscess microenvironment and persistent bacterial colonization. Herein, we present a pH-responsive supramolecular nanoplatform fabricated via single-step coassembly of cationic arginine-derived antimicrobial peptidomimetics ( AMPM -1) and natural polyphenols. This process, governed by hydrogen bonding, electrostatic interactions, and hydrophobic packing, effectively masks the cationic charges of AMPM-1, substantially reducing intrinsic hemolytic and cytotoxic properties. In vitro studies demonstrate that the assemblies maintain potent, membrane-disruptive activity against methicillin-resistant S. aureus (MRSA), including dormant and persister subpopulations. In a murine MRSA abscess model, local administration of the quercetin-based assemblies ( AMPM-1-QA ) simultaneously reduces bacterial burden and attenuates excessive inflammatory signaling. Histological examination confirms accelerated tissue regeneration, characterized by enhanced collagen deposition and anti-inflammatory macrophage polarization. By integrating acid-triggered bactericidal action with polyphenol-mediated immunomodulation, this dual-functional supramolecular strategy offers a promising approach for the stimuli-responsive treatment of recalcitrant localized infections.