Salvia miltiorrhiza -derived exosome-like nanoparticles improve diabetic cardiomyopathy by inhibiting NLRP3 inflammasome-mediated macrophage pyroptosis via targeting the NEDD4/SGK1 axis

Exosome-like nanoparticles mediate intercellular communication and regulate gene expression. In this study, we isolated and purified exosome-like nanoparticles from Salvia miltiorrhiza (SM-ELNs), a traditional Chinese medicinal herb, and investigated their therapeutic effects on diabetic cardiomyopathy (DCM). To investigate the effect of SM-ELNs on DCM, we established a mouse model via HFD/STZ treatment. Cardiac function was assessed by echocardiography. Cardiac hypertrophy was assessed by measuring the heart weight/body weight ratio and HE staining, while myocardial fibrosis was evaluated using Masson's trichrome staining. The role of SM-ELNs on NLRP3 inflammasome inhibition and macrophage pyroptosis were evaluated both in vivo and in vitro. The interaction between NEDD4 and SGK1 was analyzed by Co-IP and ubiquitination assays. SM-ELNs treatment alleviated cardiac function and histopathological changes in DCM mice. Moreover, SM-ELNs suppressed NLRP3 inflammasome activation and subsequent macrophage pyroptosis in both in vivo and in vitro models. Mechanistically, NEDD4 facilitated the ubiquitination and degradation of SGK1 in macrophages. Both NEDD4 depletion and SGK1 addition could counteract the SM-ELNs-induced suppression of NLRP3 inflammasome-triggered macrophage pyroptosis in LPS/ATP-treated RAW264.7 cells. Our study provides the first evidence that SM-ELNs inhibit NLRP3 inflammasome-mediated macrophage pyroptosis in DCM by modulating the NEDD4/SGK1 axis.