A biomimetic nanoplatform enables shTHY1-mediated immunomodulation and cartilage remodeling for osteoarthritis therapy.

Osteoarthritis (OA) is characterized by a chronic inflammatory microenvironment accompanied by elevated reactive oxygen species (ROS), synovial immune dysregulation, and progressive cartilage degeneration. While conventional pharmacological treatments often exhibit limited efficacy in halting disease advancement, we report a biomimetic, ROS-responsive nanoparticle (NPs) delivery system coated with macrophage membranes (MM-shTHY1-NPs) to achieve targeted therapy. The macrophage membrane (MM) coating not only improves retention and targeting toward inflamed synovial tissues, but also provides cytokine-scavenging capability that helps buffer the inflammatory microenvironment. Within the oxidative joint microenvironment, the ROS-responsive architecture of the NPs-facilitated by diselenide bonds-triggers the site-specific release of shTHY1 payloads. Importantly, we demonstrated the therapeutic relevance of THY1 silencing in OA microenvironment remodeling; both in vitro and in vivo experiments demonstrate that shTHY1 delivery effectively promotes macrophage repolarization from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype. This phenotypic shift subsequently remodels the chondrocyte microenvironment, suppressing matrix metalloproteinase expression and attenuating cartilage degradation. The synergy between RNAi-mediated THY1 silencing and the cytokine-scavenging capability of the macrophage membrane coating resulted in enhanced therapeutic efficacy. Our findings suggest that this cell-membrane-coated nanoplatform provides a promising strategy for the treatment of inflammatory joint diseases, with potential advantages in biosafety, site-specific delivery, and translational feasibility.