Self-assembled quercetin-zinc supramolecular nanoparticles exhibit strong antibacterial and anti-biofilm activity against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) infections remain a major public health challenge because of limited therapeutic options and the increasing prevalence of multidrug resistance. In this study, carrier-free quercetin-zinc supramolecular assemblies (Qct-Zn NPs) were fabricated through coordination-associated self-assembly and characterized using TEM, UV-Vis spectroscopy, FTIR, DLS, XPS, and zeta potential analyses. Qct-Zn NPs exhibited potent antibacterial activity against multiple MRSA clinical isolates, with enhanced efficacy compared with quercetin or ZnSO4 alone. Time-kill assays demonstrated rapid bactericidal activity, while biofilm assays revealed significant inhibition of biofilm formation and reduction of viable bacteria within mature MRSA biofilms. Mechanistic investigations suggested that Qct-Zn NP treatment was associated with membrane-associated ultrastructural changes, altered intracellular ATP levels, and ROS-associated responses. In vivo studies using murine systemic MRSA infection models showed that Qct-Zn NPs reduced bacterial burdens and systemic inflammatory responses while improving survival outcomes. Importantly, antibacterial efficacy was retained when treatment initiation was delayed to 6 h post-infection under the tested experimental conditions. Together with their favorable hemocompatibility and low cytotoxicity, these findings demonstrate that coordination-driven self-assembly of natural flavonoids and biocompatible metal ions represents a potential strategy for developing antimicrobial materials against drug-resistant staphylococcal infections.