This study investigates the therapeutic effects of magnesium (Mg) on osteoarthritis (OA), a prevalent joint disorder affecting over 250 million individuals worldwide. The research focuses on the potential of Mg to synergistically regulate both cartilage and subchondral bone, which are key components of the periarticular tissues affected by OA. The study reveals that Mg2+ promotes chondrogenic differentiation and inhibits osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), while also protecting chondrocytes from apoptosis and inhibiting osteoclast formation through the PI3K/AKT pathway. To deliver Mg2+ effectively to the joint cavity, the researchers developed poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with nano-magnesium oxide (MgO) modified with stearic acid (SA). These microspheres demonstrated significant efficacy in alleviating OA in rat models, showing promise for clinical applications. The study highlights the potential of Mg-based therapeutics to simultaneously regulate multiple tissues and cells, offering a comprehensive approach to treating OA.This study investigates the therapeutic effects of magnesium (Mg) on osteoarthritis (OA), a prevalent joint disorder affecting over 250 million individuals worldwide. The research focuses on the potential of Mg to synergistically regulate both cartilage and subchondral bone, which are key components of the periarticular tissues affected by OA. The study reveals that Mg2+ promotes chondrogenic differentiation and inhibits osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), while also protecting chondrocytes from apoptosis and inhibiting osteoclast formation through the PI3K/AKT pathway. To deliver Mg2+ effectively to the joint cavity, the researchers developed poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with nano-magnesium oxide (MgO) modified with stearic acid (SA). These microspheres demonstrated significant efficacy in alleviating OA in rat models, showing promise for clinical applications. The study highlights the potential of Mg-based therapeutics to simultaneously regulate multiple tissues and cells, offering a comprehensive approach to treating OA.