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

Summary

A fibroblast-targeted LNP delivering trans-amplifying RNA encoding collagen restored dermal ECM in vivo, with durable collagen expression up to 7 days after a single intradermal dose. It improved collagen deposition, ECM organization, and wrinkle formation in UVB photoaging models and accelerated wound closure, with minimal toxicity.

Key Findings

• Fibroblast-targeted LNPs achieved selective delivery of collagen-encoding taRNA with durable expression up to 7 days after a single intradermal dose.
• In UVB-induced photoaging models, treatment restored type I collagen deposition, normalized collagen I/III ratio, improved ECM organization, and reduced wrinkles.
• In wound models, the therapy accelerated wound closure, enhanced fibroblast migration, and increased de novo collagen deposition with minimal local/systemic toxicity.

Clinical Implications

If translated to humans, this approach could enable minimally invasive regenerative treatments for photoaging and acute wounds by directly replenishing collagen via targeted RNA delivery.

Limitations

• Preclinical study; no human or large-animal data.
• Short expression window (~7 days) and unknown immunogenicity/long-term safety.

Future Directions

Evaluate durability, dosing schedules, and safety in large-animal models; optimize taRNA payloads for broader ECM targets; and design first-in-human trials for photoaging and acute wound indications.