Targeted-Penetrating Biomimetic Hybrid Transfersomes for Enhanced Transdermal Gene Transfection in Hypertrophic Scar Therapy.

Hypertrophic scar (HS) is a recurrent and inflammatory dermal fibrotic disorder, characterized by abnormal fibroblast proliferation and excessive extracellular matrix (ECM) deposition. Affecting over 310 million patients worldwide, while effective strategies to halt progression remain lacking. The TGF-β-mediated fibrotic cascade is the central driver of HS, and siRNA-based therapeutics offer a promising gene-level intervention owing to their high sequence specificity and low off-target risk. However, siRNA translation is limited by rapid degradation, poor transfection, insufficient targeting, and the dense scar barrier that restricts noninvasive delivery. Proteomic analysis revealed that hypertrophic scar fibroblasts (HSFs) exhibit enhanced bioadhesion and protein-binding functions, with Thy-1 membrane glycoprotein highly and specifically expressed, providing a target for HSFs-active delivery. We hybridized HSFs membranes with cationic transfersomes using ultrasonic co-extrusion and achieved efficient loading of TGF-β1 siRNA through electrostatic self-assembly. This membrane-hybridized platform enabled multipathway transdermal delivery of siRNA via intercellular transport, transcytosis, and skin appendageal routes, while improving transfection, immune evasion, and homotypic targeting. Studies demonstrated efficient silencing of TGF-β1, suppression of α-SMA, ECM deposition, and pro-inflammatory cytokine release, thereby mitigating fibrotic progression. The system provides an innovative strategy for transdermal targeted siRNA therapy of HS and other skin diseases requiring genetic intervention.