Precision Nanodelivery Enables Spatiotemporal Control of NAD⁺ Metabolism in Ageing and Disease.

Declining nicotinamide adenine dinucleotide (NAD⁺) represents a conserved metabolic hallmark of ageing, organ dysfunction and numerous acute and chronic disorders. NAD⁺ metabolism exhibits pronounced spatial, cell-type and subcellular compartmentalization in pathological tissues, orchestrating DNA repair, redox homeostasis, inflammatory cascades and mitochondrial energy metabolism. Such compartment heterogeneity accounts for the inconsistent therapeutic outcomes of systemic NAD⁺ precursor supplementation, which suffers from uneven tissue distribution and insufficient subcellular metabolite restoration. While conventional precursor replenishment lays a fundamental foundation for NAD⁺ intervention, its therapeutic potency is hampered by an inability to achieve localized, time-tunable metabolic modulation. Herein, we advocate a hierarchical precision nano-delivery framework to advance NAD⁺ therapeutics beyond passive systemic supplementation toward spatiotemporally programmable metabolic regulation. Nanodelivery platforms integrate tissue penetration, cellular uptake, organelle targeting and stimulus-triggered cargo release to overcome biological barriers and match NAD⁺ modulation to defined pathological disease windows. This Review systematically summarizes cutting-edge nanodelivery strategies for tissue-, cell- and organelle-specific delivery of NAD⁺, precursors and metabolic modulators across degenerative, inflammatory and metabolic illnesses. We further discuss key translational bottlenecks, including compartment-specific biomarkers, stratified safety evaluation, rational dosage regimen, scalable production and individualized patient stratification. We argue that the next generation of NAD⁺ therapeutics will not be defined by enhanced bulk supplementation alone, but by the capacity to orchestrate precise NAD⁺ manipulation across biological space and time.