A pH/ROS dual-responsive metal-polyphenol-antibiotic nano-assembly for combating persistent infection by overcoming biofilm and cell membrane barriers.

Persistent infections are notoriously difficult to eradicate, mainly due to biofilm formation and intracellular colonization, which barrier pathogens from antimicrobials, reduce efficacy, and drive recurrence. Infection-induced inflammation further disrupts tissue homeostasis and impairs healing. To address these issues, we designed a multifunctional nanoplatform by one-step self-assembly of Zn2+, tannic acid (TA), and minocycline (MC), yielding biocompatible ZTM nanoparticles (ZTM NPs). Distinct from conventional carriers, this co-assembly strategy enables high drug loading through metal-phenolic coordination, hydrogen bonding, and π-π stacking interactions, thereby integrating MC directly into the dynamic Zn2+-TA network. Notably, the constructed ZTM NPs exhibit dual-responsive properties to the acidic pH and elevated reactive oxygen species (ROS) levels commonly present in infectious microenvironments. Functionally, ZTM NPs effectively disrupt the extracellular polymeric substance (EPS), penetrate the biofilm barrier, and eliminate embedded bacteria. Furthermore, they are capable of crossing the cell membrane barrier, facilitating efficient cellular uptake. Once internalized, the nanoparticles promote lysosomal escape, allowing the delivery of active components into the cytoplasm and contributing to the effective elimination of intracellular bacteria. Beyond antibacterial action, ZTM NPs modulate immunity by scavenging ROS, suppressing NF-κB signaling, and inhibiting M1 macrophage polarization, thereby mitigating inflammation and restoring tissue homeostasis. In vivo, they exhibit potent antibacterial and immunoregulatory efficacy, promoting periodontal regeneration. Overall, ZTM NPs represent a clinically translatable nanoplatform integrating biofilm disruption, intracellular bacterial clearance, and immune modulation.