Dermal fibroblast-targeted trans-amplifying RNA nanotherapeutics for skin extracellular matrix regeneration

Skin regeneration is fundamentally governed by the fibroblast-extracellular matrix (ECM) axis, the disruption of which often drives collagen loss and structural deterioration in skin disorders. However, current interventions typically stimulate fibroblasts indirectly and often yields modest or short-lived outcomes. mRNA therapeutics hold the potential to replenish structural proteins but are limited by poor dermal delivery and transient expression. Here we report the development of dermal fibroblast targeted lipid nanoparticle (LNP) for delivery of trans-amplifying RNA (taRNA) encoding collagen to promote ECM regeneration. This strategy markedly enhanced fibroblast-selective RNA delivery and produced sufficient and durable collagen for up to 7 days following a single intradermal dose. In UVB-induced photoaging models, this collagen taRNA delivered by fibroblast targeted LNPs restored type I collagen deposition, normalized collagen I/III ratio, improved ECM organization, and reduced wrinkle formation. In skin wound models, taRNA nanotherapeutics accelerated wound closure, promoted fibroblast migration, and increased de novo collagen deposition. Histological and biochemical analyses confirmed robust tissue remodeling with minimal local or systemic toxicity. This approach holds promise in aesthetic dermatology and skin disorders.