Polyphenol‐Driven Modular Self‐Assembled Nano‐Antibiotic for Inflammation Control via Bacterial Infection Clearance and Pyroptosis Inhibition

Abstract Bacterial infections and the resultant pyroptosis‐exacerbated inflammatory crises lead to a range of local or systemic diseases. Current therapeutic strategies are still constrained by host cellular barriers and biofilm, significantly impeding spatiotemporal precision, and functional robustness. Notably, residual pathogen‐ and damage‐associated molecular patterns can manipulate host cell biology even after antibacterial monotherapy. In this study, a modular self‐assembly strategy for the nano‐antibiotic system (EM NPs) is developed through stepwise construction design, leveraging non‐covalent interactions between polyphenol frameworks and antibiotic molecules. The assembled modules exhibit intrinsic protonation capability and strong intermolecular affinity, facilitating the dynamic modulation of molecular interactions and surface charge reversal of the EM NPs under acidic conditions. This enables intracellular delivery through adaptive drug release behavior, lysosomal escape, and efficient cytoplasmic distribution. In vitro, EM NPs leverage polyphenol‐mediated cellular barrier penetration and biofilm‐targeted accumulation, achieving superior intracellular bacterial eradication and biofilm clearance compared to free antibiotics. Furthermore, the data validates that EM NPs modulate the mitochondria‐inflammasome axis to effectively suppress pyroptosis and subsequent inflammatory responses. In mouse models of periodontitis and sepsis, EM NPs significantly alleviate inflammation and tissue damage. Overall, this work provides a promising therapeutic strategy for comprehensively managing bacterial infection‐induced inflammation.