An alkaline nanosized platelet vesicle-based hydrogel for the treatment of osteoporotic bone defects

Osteoporosis is a systemic bone disease in which excessive differentiation of osteoclasts leads to reduced bone mass, weakened bone microstructure, and increased fragility. These overactive osteoclasts require low lysosomal pH to function. Therefore, alkalinizing lysosome represents a potential therapeutic strategy for osteoporotic bone defects. Recently, platelet-derived nanovesicles have shown promise in tissue repair and drug delivery. Here, we developed nanosized platelet vesicles (NPVs) loaded with sodium bicarbonate (NaHCO₃@NPVs) for the repair of osteoporotic bone defects. These vesicles were encapsulated in an extracellular matrix hydrogel (NaHCO₃@NPVs-EH) made from fibrinogen and thrombin. When applied to bone defects, the hydrogel releases NaHCO₃@NPVs at the defect site. After being internalized by bone marrow-derived macrophages (BMDMs), NaHCO₃@NPVs can inhibit osteoclast differentiation and activity through a "biochemical dual-action" mechanism. On the one hand, NaHCO₃ can effectively alkalinize lysosomes, promote lysosomal calcium depletion, eliminate receptor activator of nuclear factor kappa-B ligand (RANKL)-induced intracellular calcium oscillations. On the other hand, the bioactive factors contained in NPVs can directly or indirectly exert an inhibitory effect on osteoclasts. <i>In vivo</i> experiments in a rat osteoporotic bone defect model revealed that the NaHCO₃@NPVs-EH reduced the number of overactive osteoclasts and enhanced bone repair. These findings suggest that NaHCO₃@NPVs-EH could be a promising tool for the treatment of osteoporotic bone defects. This study also provides a new perspective on acid-base neutralization for the treatment of osteoporosis.