A Fused Membrane‐Camouflaged Biomimetic Nanosystem for Dual‐Targeted Therapy of Septic Arthritis

Abstract Due to the inherent aseptic and enclosed characteristics of joint cavity, septic arthritis (SA) almost inevitably leads to intractable infections and rapidly progressing complex pathological environments. Presently, SA faces not only the deficient effectiveness of the gold‐standard systemic antibiotic therapy but also the scarcity of effective localized targeted approaches and standardized animal models. Herein, an ingenious multifunctional nanosystem is designed, which involves the methylation of hyaluronic acid (HA), copolymerization with DEGDA, loading with vancomycin (VAN), and then coating with fused macrophage‐platelet membrane (denoted as FM@HA@VAN). Upon intra‐articular administration, FM@HA@VAN nanoparticles exhibit sustained retention and selectively targeting to infected sites, leveraging macrophage‐mediated inflammation homing and platelet‐directed bacteria targeting. The acidic microenvironment triggers responsive release of vancomycin, leading to potent bactericidal effects. Subsequently, the exposed HA@VAN nanoparticles are efficiently internalized by activated macrophages, releasing HA to alleviate oxidative stress and achieve chondroprotection by inhibiting pro‐inflammatory cytokines, neutralizing ROS and upregulating macrophage M2 polarization. In vivo model and experiments confirm the efficacy of this dual‐targeting antibacterial approach, demonstrating its precision in eradicating bacterial infections and alleviating associated pathological processes, including synovial hyperplasia and cartilage erosion. The dual‐targeting therapeutic nanosystem, coordinated with fused‐membranes, holds promise for enhancing the treatment efficacy of SA.