Objective: Nicotinamide riboside (NR) is neuroprotective; however, its low permeability through the blood -brain barrier restricts its therapeutic ef ficacy in central nervous system diseases. Compared with oral NR administration, liposome-based NR loading is hypothesized to improve its pharmacological properties during cerebral ischemia, especially when administered intravenously. Methods: NR chloride (NRC) was encapsulated in an optimized liposome composition and administered by bolus intravenous injection. This was followed by examination of its pharmacokinetics, organ distribution, and effects on cerebral ischemia in mice. Results: Compared with conventional NRC solution, the liposome form led to a 2.76-fold higher C max and a 5.32-fold higher AUC 0 e24h in plasma after a bolus injection of 40 mg/kg. In healthy mouse brain, it caused a signi ficant elevation of C max (2.93-fold) and AUC 0.25 e24h (2.68-fold). In cerebral ischemia model mice, NRC liposomes increased the drug concentration at 1 and 6 h post-ischemia, increased tissue NAD + and ATP levels, reduced infarct volume (by a further decrease of 35.4%), ensured neuronal survival, attenuated glial activation, and signi ficantly improved behavioral recovery compared with conventional NRC treatment. Conclusion: Liposome loading enhances the brain distribution and therapeutic effects of NRC, which strengthens its possibility for clinical translation and neurorestoration in stroke. (c) 2024 Published by Elsevier Ltd on behalf of Tsinghua University Press. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).