Dual Antifibrotic Modulation via CTGF Silencing and Peptide Amphiphile Nanofibers for Topical Treatment of Skin Fibrosis

Abstract Skin fibrosis is driven in part by transforming growth factor-β (TGF-β) signaling and the matricellular protein connective tissue growth factor (CTGF). Elevated CTGF expression is a hallmark of fibrotic skin lesions and contributes to pathological extracellular matrix remodeling. In this project, an antisense oligonucleotide (AON) delivery system was developed for the treatment of skin fibrosis. In this respect, two antifibrotic agents, i) AON against CTGF and ii) antifibrotic polypeptide amphiphile, were self-assembled into nanofibers to enhance antifibrotic efficacy. The nanofibers were encapsulated in chitosan nanoparticles (CNPs) for protection and sustained release. Loaded CNPs were characterized by morphology, size, endosomal escape, and skin penetration using a transwell-based 3D skin model. The nanoparticles exhibited an average size of 220 nm. The encapsulation efficiency of CNPs was 52%, providing sustained nanofiber release over 7 days. With the use of nanoparticles, clear reduction trends were observed in CTGF, α-smooth muscle actin (αSMA), and collagen expression. CNPs penetrated the skin model gradually, revealing no cytotoxicity to skin cells. Overall, these results reveal the potential of the designed nanofibers as a therapeutic agent and the CNPs as the carrier of the nanofibers. The developed delivery system can be used as an alternative approach for the treatment of lesions in fibrotic skin.