Ion-coupled transfersome complexes for enhanced transdermal NAD+ repletion and mitigation of cellular senescence signatures.

Nicotinamide adenine dinucleotide (NAD+) is a pivotal coenzyme whose decline drives mitochondrial dysfunction and senescence. However, NAD+ delivery to skin is limited by poor stability and tissue accessibility. Here, we develop an ion-coupled NAD+ transfersome (ICoN) that stabilizes NAD+ and enables efficient, non-invasive transdermal delivery. ICoN restores intracellular NAD+ levels and reverses transcriptomic programs associated with DNA damage, oxidative stress, and senescence in vitro. Functionally, ICoN promotes mitochondrial functional integrity and sustains proliferative and migratory competence under senescent and NAD+-depleted conditions. In ex vivo porcine and human skin explants, ICoN achieves superior intratissue NAD+ penetration while attenuating senescent signatures compared with free NAD+ or precursors. Integrated high-spatial-resolution transcriptomic profiling and bulk transcriptomic analyses of UV-stressed human skin reveal that ICoN mitigates histological disruption and senescence-associated transcriptional programs at the tissue level. Moreover, ICoN extends lifespan and enhances healthspan in C. elegans. These findings characterize ICoN as a transdermal NAD + delivery platform supporting localized NAD + restoration in the context of skin aging.