Denosumab-functionalized nanoparticles target macrophages to mitigate age-related osteoarthritis and osteoporosis.

Osteoarthritis (OA) and osteoporosis (OP) are prevalent degenerative diseases in the elderly population, often coexisting and sharing a common pathogenic mechanism involving the receptor activator of nuclear factor κB ligand/receptor activator of nuclear factor κB (RANKL/RANK) signaling pathway. Denosumab (DS) has shown efficacy in treating OA and OP. This study aimed to investigate the mechanism through which DS mitigates age-related OA-OP by regulating macrophage polarization. Due to the poor targeting ability of DS to macrophages, we have prepared folate-modified liposomes (Lip-FA) loaded with DS (DS@Lip-FA) target macrophage nanoparticles. Using humanized mouse models of aging, we observed DS@Lip-FA effects on macrophage polarization and the subsequent impact on cartilage and bone tissues. Our results reveal that aging led to an increase in the pro-inflammatory M1 macrophages and a decrease in the anti-inflammatory M2 macrophages in both bone and cartilage tissues, which is correlated with elevated RANKL expression. DS@Lip-FA treatment effectively decreased the number of M1 macrophages and increased the number of M2 macrophages. This shift in macrophage polarization reduced chondrocyte apoptosis, promoted bone marrow mesenchymal stem cell (BMSC) proliferation and osteogenic differentiation, and reduced chondrocyte and BMSC senescence. These findings indicate that DS@Lip-FA exerts its therapeutic effects on age-related OA-OP by regulating macrophage polarization and suggest that DS@Lip-FA is a promising treatment for this complex condition in the elderly population.