Magnolol nanoparticles combat MRSA by disrupting TCA cycle and arginine metabolism to induce oxidative stress.

Plant-derived bioactive compounds are promising antimicrobial candidates due to their diverse bioactivities and low propensity for inducing bacterial resistance. However, the clinical translation of magnolol (MG) is hindered by its poor aqueous solubility, low bioavailability, and non-negligible cytotoxicity. Here, core-shell magnolol nanoparticles (MGs) were developed via self-assembly of MG, polyvinylpyrrolidone (PVP), and bovine serum albumin (BSA). This formulation significantly improved aqueous stability and sustained release, enhanced drug-bacteria interactions, while concomitantly reducing toxicity. In vitro, MGs exhibited enhanced antibacterial activity against Methicillin-Resistant Staphylococcus aureus (MRSA), with minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) values of 15.625 µg/mL and 31.25 µg/mL, approximately half of the values observed for free MG. In vivo studies further demonstrated superior therapeutic efficacy with improved biocompatibility. Mechanistically, MGs disrupted the tricarboxylic acid (TCA) cycle and arginine metabolism, promoted reactive oxygen species (ROS) accumulation, depleted superoxide dismutase (SOD) activity, and induced oxidative stress-mediated bacterial death. These findings highlight MGs as a promising strategy for treating drug-resistant infections through bacterial metabolic modulation.