Sirt3 Genetically Engineered Apoptotic Bodies Alleviate Skeletal Aging by Limiting Aggravated NLRP3 Inflammasome...

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.