Facile Fabrication of Multifunctional Metal-Phenolic Network Nanoparticles for Bacterial Keratitis Treatment

The management of methicillin-resistant Staphylococcus aureus (MRSA) keratitis remains highly challenging due to escalating antibiotic resistance and the severe, vision-threatening damage driven by uncontrolled inflammation. In this work, EGCG-Zn-VAN nanoparticles (NPs) were engineered as a multifunctional metal-phenolic network (MPN)-based platform to overcome these limitations through three integrated mechanisms: enhanced ocular retention, infection microenvironment-responsive antibiotic release, and synergistic anti-inflammatory activity. The carrier, formed by coordination-driven self-assembly of (-)-epigallocatechin gallate (EGCG) and Zn²⁺, enabled high vancomycin loading and provided prolonged precorneal residence. A checkerboard assay confirmed potent pharmacological synergy between the MPN matrix and vancomycin, while the platform exhibited robust pH-responsive behavior for preferential drug release under acidic infectious conditions. In a rat MRSA keratitis model, EGCG-Zn-VAN NPs combined potent bactericidal efficacy with effective modulation of the oxidative and inflammatory milieu. Notably, despite delivering a substantially lower antibiotic dose (∼14.9 μg/mL), the nanoparticle formulation significantly outperformed a clinical standard-of-care comparator (5% free vancomycin), achieving >95% reduction of MRSA burden and suppressing pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) toward near-baseline levels. Quantitative histomorphometry confirmed that treatment led to the preservation of corneal transparency, epithelial integrity, and physiological stromal thickness. These outcomes arise from the cooperative interplay between vancomycin and the ROS-scavenging EGCG-Zn network, establishing EGCG-Zn-VAN NPs as a versatile, stimuli-responsive nanotherapeutic platform capable of addressing both microbial burden and host pathology. This platform provides a promising dose-sparing strategy for the clinical management of drug-resistant bacterial keratitis and other inflammation-associated ocular infections.