Trojan horse-inspired vaccine-like nanoparticle with enhanced lubrication and active-passive synergistic anti-inflammation for post-traumatic osteoarthritis treatment.

Post-traumatic osteoarthritis (PTOA) is initiated by joint injury and progresses through the interaction of abnormal mechanical loading, oxidative stress, inflammation, and extracellular matrix degradation. Early intra-articular intervention is greatly limited by rapid clearance, insufficient lubrication, and dynamically evolving inflammatory microenvironment. Here, we developed a Trojan horse-inspired vaccine-like nanoparticle, PDMI, integrating immune-evasive retention, hydration lubrication, intrinsic reactive oxygen species (ROS) consumption, and ROS-responsive icariin (ICA) release. The hydrated exterior reduced macrophage recognition and interfacial shear, whereas the catechol groups and phenylboronic ester linkages consumed ROS and enabled microenvironment-responsive ICA release, respectively. PDMI reduced the coefficient of friction in simulated synovial fluid by approximately 52.07% at 3 N and 3 Hz and achieved coefficients of friction on the order of 0.001 under the tested microscale conditions. Intra-articular fluorescence imaging showed an apparent retention half-life of 22.93 days for PDMI, approximately 8.9-fold longer than that of free Cy5. In chondrocytes, PDMI reduced mitochondrial ROS, preserved mitochondrial membrane potential, restored NRF2-mediated antioxidant defense, and suppressed NF-κB/IκBα pathway activation and downstream inflammatory cytokine expression. In a 4-week rat PTOA model, the single intra-articular administration attenuated osteophyte formation and abnormal subchondral bone remodeling, reduced the OARSI score by more than 80%, decreased MMP-13 expression, and preserved glycosaminoglycan and Col2α levels. These findings position PDMI as a promising multifunctional intra-articular platform for early PTOA intervention and provide a foundation for its further translational development.