NAD+ metabolic restoration resolves the inflammation-immunocompetence trade-off in lung graft-versus-host disease.

Chronic lung graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains difficult to treat, and broad immunosuppression increases infection risk. Single-cell profiling of bronchoalveolar lavage from bronchiolitis obliterans lesions revealed collapse of an epithelial nicotinamide adenine dinucleotide (NAD+) metabolic axis with pathogenic immune-epithelial remodeling, nominating NAD+ restoration as an entry point. Because free NAD+ is poorly cell-permeable and rapidly consumed, we engineered CaNAD+-PGB-LiP (CNAPL), a high-payload NAD+ nanomedicine enabling direct intracellular replenishment. In murine allo-HSCT GVHD, CNAPL improved clinical scores and survival, reduced vascular and epithelial injury, and curtailed hyperinflammation and effector overactivation across GVHD target organs. Unlike immunosuppression, CNAPL preserved phagocytosis, NK/NKT cell (natural killer/natural killer T cell) cytotoxicity, and T cell memory. In posttransplant influenza or Klebsiella infection, CNAPL maintained pathogen control without rekindling GVHD, decoupling inflammation control from infection susceptibility. This metabolism-centered, host-directed strategy restores immune-tissue homeostasis and provides a practical translational path for durable lung GVHD control with preserved antimicrobial defense.