Senescence‐Targeted and NAD+‐Dependent SIRT1‐Activated Nanoplatform to Counteract Stem Cell Senescence for Promoting Aged Bone Regeneration

Abstract Age‐related bone defects are a leading cause of disability and mortality in elderly individuals, and targeted therapy to delay the senescence of bone marrow‐derived mesenchymal stem cells (MSCs) has emerged as a promising strategy to rejuvenate bone regeneration in aged scenarios. More specifically, activating the nicotinamide adenine dinucleotide (NAD + )‐dependent sirtuin 1 (SIRT1) pathway is demonstrated to effectively counteract MSC senescence and thus promote osteogenesis. Herein, based on an inventively identified senescent MSC‐specific surface marker Kremen1, a senescence‐targeted and NAD + dependent SIRT1 activated nanoplatform is fabricated with a dual delivery of resveratrol (RSV) (SIRT1 promoter) and nicotinamide riboside (NR, NAD + precursor). This targeting nanoplatform exhibits a strong affinity for senescent MSCs through conjugation with anti‐Kremen1 antibodies and enables specifically responsive release of NR and RSV in lysosomes via senescence‐associated β‐galactosidase‐stimulated enzymatic hydrolysis of the hydrophilic chain. Furthermore, this nanoplatform performs well in promoting aged bone formation both in vitro and in vivo by boosting NAD + , activating SIRT1, and delaying MSC senescence. For the first time, a novel senescent MSC‐specific surface marker is identified and aged bone repair is rejuvenated by delaying senescence of MSCs using an active targeting platform. This discovery opens up new insights for nanotherapeutics aimed at age‐related diseases.