mRNA Therapeutics for Skin Rejuvenation: From Aging Atlases to Clinical Translation.

Skin aging is a multifactorial process characterized by the progressive decline of tissue structure, function and regenerative capacity. Although numerous interventions have been developed to improve the clinical manifestations of aging, most primarily alleviate downstream consequences rather than directly targeting the molecular mechanisms underlying tissue deterioration. Recent advances in single-cell and spatial transcriptomic technologies have fundamentally transformed our understanding of skin aging by identifying cell type-specific transcriptional programmes and uncovering novel regulators of epidermal homeostasis, dermal remodelling and intercellular communication. These high-resolution atlases have generated an expanding repertoire of candidate rejuvenation targets, many of which consist of intracellular regulatory proteins that have traditionally been considered difficult to manipulate using conventional pharmacological approaches. In parallel, rapid progress in RNA engineering has established nucleic acid therapeutics as a versatile approach for precise molecular intervention. Among these, messenger RNA (mRNA) therapeutics are particularly well suited to the molecular landscape emerging from skin aging atlases because they enable transient restoration of proteins that are lost during aging. Advances in lipid nanoparticles, extracellular vesicles and microneedle-based delivery systems are rapidly improving the feasibility of local cutaneous administration. In this review, we discuss the emerging rejuvenation targets identified by single-cell and spatial transcriptomic atlases and examine recent advances in RNA-based therapeutics and mRNA delivery strategies that are paving the way for precision skin rejuvenation.