Biomaterials Targeting Mitochondrial NAD⁺ Metabolism for Tissue Regeneration

Mitochondrial nicotinamide adenine dinucleotide (NAD⁺) has emerged as a pivotal regulator in tissue regeneration, central to cellular energy metabolism and redox homeostasis. It regulates key mitochondrial processes-including energy production, reactive oxygen species (ROS) scavenging, and cell death-primarily through the tricarboxylic acid cycle (TAC), oxidative phosphorylation, and sirtuin deacetylase activity. This coordinated regulation fosters a favorable metabolic and immune microenvironment conducive to tissue repair. Strategies to increase mitochondrial NAD⁺ levels, such as delivery, precursor supplementation (e.g., NR or NMN), catalytic conversion, and inhibition of NAD⁺-consuming enzymes, have demonstrated significant efficacy in promoting regeneration across diverse tissues, including bone, cartilage, tooth, skin, myocardium, muscle, nerve, and vascular. There is no review that systematically addresses the latest progress in the advances of biomaterials targeting mitochondrial NAD⁺ metabolism for tissue regeneration. This review fills the gap by outlining the central role of biomaterials targeting mitochondrial NAD⁺ in tissue regeneration. We introduce the biological functions and regulatory mechanisms of mitochondrial NAD⁺, highlight the intervention strategies to boost NAD⁺ levels, and summarize the applications across diverse regenerative contexts. Finally, we discuss prevailing challenges and future prospects, providing new theoretical and interventional insights for regenerative medicine.