Sirt3 Genetically Engineered Apoptotic Bodies Alleviate Skeletal Aging by Limiting Aggravated NLRP3 Inflammasome Activation of Senescent Macrophages

ABSTRACT Skeletal aging is characterized by increased fragility, reduced bone mass, and deterioration of bone microstructure. Although aging‐related immune dysfunction of macrophages, namely immunosenescence, is known to contribute to this process, the underlying mechanism remains poorly understood. Here, we find that the senescence of macrophages leads to a decrease in the expression of Sirtuin3 (Sirt3), which in turn leads to increased basal and lipopolysaccharides (LPS)‐induced protein expression of NLRP3 and facilitates the assembly of NLRP3 inflammasome in macrophages that mediates aging‐related osteoporosis. Given the phagocytic property of macrophages, we develop a genetically engineered apoptotic body‐based platform for targeted delivery of Sirt3 to macrophages and verify that Sirt3‐enriched apoptotic bodies (ABs‐Sirt3) delay skeletal aging by promoting ubiquitination and degradation of NLRP3. Our work reveals that Sirt3 plays a key role in regulating aggravated inflammatory responses that accelerate skeletal aging during macrophage senescence and illustrates a novel nanotechnology‐based therapeutic approach targeting immune senescence‐induced acceleration of skeletal aging, which may provide potential therapeutic value for human patients with age‐related osteoporosis.