Hydrated microRNA-regulating nanoplatform for synergistic lubrication and anti-inflammation to alleviate osteoarthritis

Osteoarthritis (OA) remains a major clinical challenge, lacking effective disease-modifying therapies. The pathological progression of OA is fueled by the vicious loop involving cartilage wear-and-tear and macrophage-mediated synovitis, necessitating a treatment that simultaneously provides lubrication and anti-inflammatory effects. Herein, we present a novel hydrated nano-delivery system loaded with the miRNA-let-7c plasmid (HydroMiR) that offers a dual-action strategy. HydroMiR could exhibit prolonged retention and enhanced aqueous lubrication within the joint cavity, preserving the viscoelasticity of synovial fluid and restoring lubrication and shock absorption. Subsequently, it underwent programmable unlocking and charge reversal in response to macrophage extracellular and intracellular microenvironments, thereby achieving precise and potent miRNA regulation via macrophage-specific active and passive endocytosis, cellular uptake, and lysosomal escape. The markedly amplified miR-let-7c expression via HydroMiR ensures sustained and vigorous repolarization of macrophages to the anti-inflammatory M2 phenotype, effectively controlling cytokine secretion and indirectly promoting chondrocyte migration, proliferation, differentiation, and cartilage matrix synthesis. Intra-articular injection of HydroMiR significantly alleviates surgery-induced synovial inflammation, cartilage degeneration, and subchondral bone sclerosis. This dual-function and self-assembling gene delivery nanoplatform disrupts the OA vicious cycle, providing long-term therapeutic benefits for OA through sustained hydration, lubrication, and anti-inflammation.