Membrane Fusion-Based Mirabilis Himalaica-Derived Exosome-like Nanoparticles Fused with Cell-Penetrating Peptide...

Exposure to ultraviolet (UV), particularly UVA radiation, is a primary driver of photoaging due to its deep dermal penetration, which triggers DNA damage, collagen degradation, and immune suppression. Chebulinic acid (CA), a polyphenolic compound from Terminalia chebula, exhibits potent antioxidant and anti-inflammatory properties against UVB-induced skin damage. However, its large molecular weight hinders transdermal delivery and the TAT_47-57 peptide (core of HIV-1 TAT) enables rapid transmembrane transport. Large particles with double-layer membrane structure and a diameter exceeding 1000 nm were obtained during the separation of plant-derived exosome-like nanoparticles (PELNs), which are not considered as PELNs (50-500 nm), after a mixture with TAT anchored to the surface of engineered artificial vesicles (EAVs) and extrusion causes membrane fusion, employed as novel nanocarriers to overcome the difficulty in skin penetration by leveraging their lipid bilayer structure and surface membrane-anchored TAT for efficient epidermal fusion and intercellular penetration. Furthermore, CA-loaded TAT-ePELNs demonstrate significant efficacy in mitigating UVA-induced photoaging. Collectively, this study expands the anti-UVR damage application spectrum of CA from UVB to UVA exposure and establishes a green, efficient, and biosafe strategy for transdermal drug delivery by utilization of non-PELNs generated during the preparation process of PELNs.