Targeted NAD⁺ Metabolic Reprogramming Enables Functional Endometrial Regeneration and Fertility Restoration in...

Regeneration of the injured endometrium requires re-establishment of a permissive microenvironment that supports coordinated epithelial renewal, angiogenesis, and matrix remodeling. However, this regenerative transition remains incomplete in intrauterine adhesions, suggesting that insufficient metabolic support may represent an underappreciated barrier to functional repair. Here, we show that an inflammation-homing biomimetic nanoplatform enables preferential NMN delivery to the injured uterus, restoring mitochondrial membrane potential, the NAD⁺/NADH ratio, and ATP production in metabolically compromised epithelial cells. Treatment was associated with epithelial proliferation, angiogenic responses, reduced myofibroblast activation, and decreased collagen accumulation. Transcriptomic profiling revealed broad changes from inflammation- and fibrosis-associated signaling toward a more regeneration-permissive state. In a murine model, treatment increased endometrial thickness, gland number, and vascular density, reduced fibrosis, and improved embryo implantation and live-birth outcomes; pup body weight at postnatal day 12 did not differ detectably among groups. These findings support spatially controlled NAD⁺ delivery as a promising metabolism-oriented strategy for endometrial regeneration.