Engineered magnesium oxide (MgO) nanoparticles modified with stearic acid (SA) and encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres (MgO&SA@PLGA) were developed for the treatment of osteoarthritis (OA). The study demonstrated that Mg²⁺, delivered via these microspheres, effectively protected both cartilage and subchondral bone in rat models of OA. The therapeutic effect was mediated through the PI3K/AKT pathway, which regulated chondrogenic differentiation, inhibited osteogenic differentiation, and reduced chondrocyte apoptosis. The MgO&SA@PLGA microspheres provided a sustained release of Mg²⁺ in the joint cavity, maintaining a stable pH environment and enhancing the therapeutic effect. In vivo experiments showed that the microspheres significantly improved gait symmetry, reduced pain, and protected cartilage and subchondral bone from OA damage. The MPs were biocompatible, with no adverse effects on major organs. The study highlights the potential of Mg²⁺-based therapies for synergistic treatment of cartilage and bone in OA, offering a promising approach for clinical translation. The findings suggest that Mg²⁺ can regulate multiple tissues and cells, providing a novel strategy for OA treatment.Engineered magnesium oxide (MgO) nanoparticles modified with stearic acid (SA) and encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres (MgO&SA@PLGA) were developed for the treatment of osteoarthritis (OA). The study demonstrated that Mg²⁺, delivered via these microspheres, effectively protected both cartilage and subchondral bone in rat models of OA. The therapeutic effect was mediated through the PI3K/AKT pathway, which regulated chondrogenic differentiation, inhibited osteogenic differentiation, and reduced chondrocyte apoptosis. The MgO&SA@PLGA microspheres provided a sustained release of Mg²⁺ in the joint cavity, maintaining a stable pH environment and enhancing the therapeutic effect. In vivo experiments showed that the microspheres significantly improved gait symmetry, reduced pain, and protected cartilage and subchondral bone from OA damage. The MPs were biocompatible, with no adverse effects on major organs. The study highlights the potential of Mg²⁺-based therapies for synergistic treatment of cartilage and bone in OA, offering a promising approach for clinical translation. The findings suggest that Mg²⁺ can regulate multiple tissues and cells, providing a novel strategy for OA treatment.