A sustained NAD⁺ supplementation-biosynthesis nanoplatform for metabolic restoration in aged bone regeneration

Increasing NAD⁺ levels has demonstrated promising therapeutic potential for treating aging-related skeletal disorders. However, for existing bone defects in aged individuals, it remains a formidable challenge to achieve localized and sustained NAD⁺ restoration while overcoming poor NAD⁺ delivery efficiency and impaired endogenous biosynthesis in senescent cells. Herein, this study developed a sustained NAD⁺ supplementation-biosynthesis nanoplatform, N/S@M@P, to stimulate aged bone regeneration. This platform employs dual-mesoporous silica nanoparticles to highly load NAD⁺ and controllably load NAD⁺ biosynthesis activator, establishing a "supplementation-biosynthesis" strategy for rapid NAD⁺ replenishment and sustained NAD⁺ metabolic restoration in senescent bone marrow-derived mesenchymal stromal cells (BMSCs). Meanwhile, N/S@M enhanced cellular uptake efficiency by 41.0% through regulating the endocytic pathways of senescent BMSCs. After incorporation into an injectable hydrogel scaffold, N/S@M@P enabled sustained particle release over 14 days, supporting prolonged metabolic restoration. This strategy increased the NAD⁺/NADH ratio by 11.2-fold and increased ATP production by 3.25-fold in senescent BMSCs. In aged bone defects, N/S@M@P reduced the proportion of senescent BMSCs to 21.2% at day 7 and increased the bone volume fraction (BV/TV) by 119% at 4 weeks. These findings demonstrate that this nanoplatform can effectively restore the functions of senescent BMSCs, providing a promising therapeutic strategy for aging-related bone regeneration.