Nanoconfinement Engineering of Ultrasmall AgNPs on Bioengineered Zein–Polydopamine Nanostructure for Synergistic Photothermal and Sustained Antibacterial Therapy

Bacterial infections, especially those caused by drug-resistant strains, pose severe threats due to their recalcitrance to eradication, leading to persistent inflammation, delayed healing, and elevated therapeutic burdens. Developing scalable, biocompatible platforms capable of achieving rapid sterilization and long-term antibacterial efficacy with precise control remains a critical challenge. Here, we present a bioengineered nanocomposite (AgNPs@ZP) by integrating zein nanoparticles as bio-nanotemplates for spatially controlled polydopamine (PDA) deposition, followed by <i>in situ</i> synthesis of ultrasmall silver nanoparticles (AgNPs) through a domain-confined ligand-rich surface microenvironment. This hierarchical architecture synergized photothermal and sustained antibacterial functionalities, achieving an ultralow minimum bactericidal concentration (MBC) of 0.0625 μg/mL against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) below the WHO permissible limit for silver in drinking water (0.1 μg/mL). The ordered PDA framework and densely anchored AgNPs enhanced the photothermal conversion efficiency (PCE) to 49.79% via localized surface plasmon resonance (LSPR)-induced electric field amplification and collective heating effects. Under near-infrared (NIR) irradiation, AgNPs@ZP exhibited complete eradication of high bacterial loads simulating clinically severe infections (approximately 8log₁₀ CFU/mL reductions) within 20 min. <i>In vivo</i>, AgNPs@ZP-embedded carbomer gel combined with NIR therapy accelerated the healing of MRSA-infected wounds, accompanied by outstanding bacterial elimination, suppressed inflammation, enhanced tissue regeneration, and robust biosafety. This dual-modal nanoplatform leveraged the structural advantages of natural protein-based nanoparticles to enable precise integration of photothermal and AgNP-mediated antibacterial functionalities, offering a biocompatible and eco-friendly strategy against refractory drug-resistant infections.