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This study reveals that nicotinamide (NAM) levels in PE\u2010derived pEVs (PE\u2010EVs) are lower than in pEVs from normal pregnancies, correlating with disease severity. Functionally, NAM in pEVs inhibits Th1 differentiation via SIRT1 suppression and Th17 differentiation via macrophages. NAM\u2010deficient pEVs exhibit reduced capacity to inhibit Th1 and Th17 cell differentiation both in vitro and in vivo, leading to PE\u2010like symptoms. NAM is enriched in pEVs compared to placental villous tissue and maternal serum. The lower NAM in PE\u2010EVs is due to decreased hepatocyte growth factor\u2010regulated tyrosine kinase substrate (HRS) expression in trophoblasts, which loads NAM into the cargo of multivesicular bodies (MVBs) via binding to the tryptophan\u2010115 residue of HRS. Furthermore, the reduction of HRS in PE trophoblasts results from ubiquitination and degradation by elevated HSP27. 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