A TiVCrMoC3 MXene-Based Sustained-Release Vancomycin Nanoplatform Mitigates Septic Arthritis through Modulation of Bacterial Acetate Metabolism

Acute septic arthritis caused by bacterial infection is a common and serious orthopedic disease. The formation of bacterial biofilms severely limits antibiotic penetration, rendering conventional therapy ineffective and short‑acting. In this study, we developed a novel nanodrug delivery system by loading vancomycin onto high‑entropy TiVCrMoC3 MXene (VCM@NPs). Featuring a sheet‑like porous structure, this material enables efficient drug loading via electrostatic interactions and sustains release in the weakly acidic infection microenvironment, achieving a cumulative release of 67% over 20 days. In vitro, VCM@NPs exhibited potent bactericidal activity against Staphylococcus aureus, with complete colony eradication by day 5, and markedly disrupted biofilm architecture, as shown by electron and confocal microscopy. In a rat septic arthritis model, a single intra‑articular injection of VCM@NPs effectively inhibited bacterial growth, alleviated joint inflammation, and improved cartilage and bone damage. By day 10, OARSI scores in the VCM@NPs group were significantly lower than those in the free vancomycin group, and micro‑CT analysis revealed increased bone volume and trabecular thickness, confirming sustained therapeutic efficacy. Notably, mass spectrometry imaging demonstrated that VCM@NPs reprogrammed the joint metabolic microenvironment by suppressing the bacterial acetate metabolic pathway, thereby destabilizing biofilms-a mechanism that, to the best of our knowledge, has not been previously reported in the context of nanoparticle-mediated modulation of this pathway. Collectively, this study offers a new nanodrug delivery strategy that integrates sustained release with biofilm disruption, holding promise for clinical translation in septic arthritis.