MSC-derived exosomes ameliorate systemic lupus erythematosus by reprogramming macrophage mitochondrial homeostasis via the CMPK2-cGAS-STING axis.

Mesenchymal stem cell-derived exosomes (MSC-exo), natural functional nanovesicles, are considered a potent alternative for MSC therapy for the treatment of systemic lupus erythematosus (SLE); however, the molecular mechanisms underlying their therapeutic effects remain elusive. Here, we report that cytidine/uridine monophosphate kinase 2 (CMPK2) is markedly upregulated in monocytes/macrophages from both SLE patients and murine lupus models. CMPK2 overexpression promoted M1 macrophage polarization and induced mitochondrial dysfunction, leading to activation of the cGAS-STING pathway. Conversely, CMPK2 knockdown potently suppressed cytoplasmic mtDNA release and abrogated the induction of cGAS, STING, and IFN-β in macrophages stimulated with LPS/IFN-γ. Treatment with MSC-exo markedly ameliorated disease progression in lupus-prone mice and reprogrammed macrophage phenotypes in splenic and renal microenvironments. Mechanistically, MSC-exo downregulated CMPK2 expression and attenuated cGAS-STING activation, thereby restoring mitochondrial integrity as evidenced by increased mitochondrial mass, reduced mitochondrial ROS generation, and recovery of mitochondrial membrane potential. Our findings uncover a key mechanism through which MSC-exo modulate immune and inflammatory responses in SLE, providing a mechanistic foundation for their therapeutic application and highlighting CMPK2 as a potential target for future biomarker-driven and bioengineering-enhanced treatment strategies.