Metabolic Nanomedicine Reprograms Mesenchymal Stem Cells for Durable Exosome‐Mediated Immunomodulation

Mesenchymal stem cells (MSCs) are widely recognized for their immunomodulatory potential, yet their clinical efficacy remains inconsistent due to poor persistence and functional instability under prolonged inflammatory stress. Here we identify NAD + depletion as a central driver of MSCs exhaustion, leading to metabolic collapse, programmed cell death, and loss of immunoregulatory activity. Direct restoration is nontrivial, because NAD + is membrane impermeable and extracellularly unstable. To overcome this barrier, we developed a nanoparticle system for efficient intracellular delivery of NAD + , enabling sustained metabolic support even under hostile inflammatory conditions. NAD + restoration markedly improved MSCs survival, preserved their ability to suppress T cell proliferation, and enhanced therapeutic efficacy in murine colitis. Mechanistically, NAD + supplementation did not increase anti‐inflammatory mediator release but instead reprogrammed exosome function, enhancing secretion and selectively enriching key anti‐inflammatory microRNAs. This effect was mediated by an NAD + /α‐ketoglutarate/TET1‐SMPD3 axis involving promoter demethylation, exosome biogenesis, and microRNA sorting. Together, these findings uncover an epigenetic‐metabolic circuit that links NAD + availability to exosome‐mediated immune regulation, providing a mechanistic foundation for developing metabolically fortified MSCs platforms with enhanced persistence and translational potential in inflammatory disease.