Oral delivery of carrier-free dual-drug nanocrystal self-assembled microspheres improved NAD+ bioavailability and attenuated cardiac ischemia/reperfusion injury in mice

Nicotinamide riboside (NR), as a dietary supplement, can be converted to nicotinamide adenine dinucleotide (NAD⁺) in cells to support mitochondrial energy metabolism. However, the efficacy of oral administrated NR is limited due to its quick degradation in circulation and low bioavailability in targeted organs. In this study, we fabricated nanocrystal self-assembled microspheres by Nano Spray Dryer for oral delivery of NR. The structure of NR and resveratrol (RES) nanocrystal self-assembled microspheres (NR/RESms) is confirmed by the morphology, chemical structure, and crystallization. The NR/RESms displayed restricted NR release at the gastric acid-mimic condition (<15% in the first 8 hours), while achieved accelerated NR release in an enteric-mimic environment (>46% within 8 hours). Oral administration of NR/RESms for 8 hours significantly elevated NAD⁺ levels in serum (169.88 nM versus 30.93 nM in the NR group, p < .01; and 66.89 nM in the NR + RES group, p < .05), and enhanced NAD⁺ abundance in multiple organs in mice, exhibiting an improved oral NAD⁺ bioavailability. In addition, without any serious adverse effects on major organs, oral delivery of NR/RESms attenuated myocardial infarction (15.82% versus 19.38% in the I/R + NR group and 20.76% in the I/R + NR + RES group) in a cardiac ischemia/reperfusion (I/R) injury mouse model. Therefore, our data supported that the NR/RESms is a promising candidate as NAD⁺ booster for oral administration.