Spatiotemporal-adaptive nanotherapeutics promote post-injury regeneration in ageing through metabolic modulation.

In the elderly population, dysregulated cellular behaviour during the healing process impacts tissue regeneration after injury. Early in the regeneration process, pro-inflammatory macrophages contribute to immune imbalance, while in later stages, senescent stem cells reduce regenerative capacity. Here we demonstrate that nicotinamide adenine dinucleotide (NAD+) can reprogramme both types of dysfunctional cell. We developed a spatiotemporal-adaptive nanotherapeutic system for the delivery of NAD+ into selected cells during different phases of tissue repair. By replenishing intracellular NAD+ pools, this system reshapes the multicellular regeneration niche, by metabolically rewiring pro-inflammatory macrophages towards a pro-repair phenotype during the early phase, and enhancing the differentiation capacity of senescent stem cells at later stages. This strategy effectively restored impaired bone regeneration in osteoporotic mice and accelerated skin wound healing. Our work presents a spatiotemporal-adaptive nanomedicine platform that bridges cell metabolism, nanomedicine and regeneration therapy.