A bioengineered extracellular vesicle-based platform for targeted codelivery and multi-mechanistic therapy of skin...

Systemic sclerosis (SSc) is an autoimmune fibrotic disease with limited effective therapies. Kaempferol (K) has promising antifibrotic activity but is limited by poor solubility and delivery efficiency. In this study, we prepared kaempferol-loaded liposomes via the thin-film dispersion method, extracted exosomes by ultracentrifugation combined with PEG precipitation, and successfully constructed kaempferol-loaded liposome-exosome composite nanoparticle (KLE) through repeated freeze-thaw fusion.Characterization showed KLE had ideal physicochemical properties with an average particle size of 189.87 ± 12.62 nm, PDI of 0.40 ± 0.09, and encapsulation efficiency of 66.00 ± 3.07%. KLE exhibited sustained release behavior in vitro and enhanced DPPH radical scavenging capacity (55.92 ± 4.34% at 0.2 mg/mL) by activating the Nrf2/ARE antioxidant pathway. In a bleomycin-induced mouse model of localized scleroderma, topical administration of KLE significantly reduced dermal thickening, collagen deposition, and inhibited myofibroblast activation. It also downregulated TGF-β/Smad signaling, reduced pro-inflammatory factors, and regulated VEGF expression.This study demonstrates that KLE synergizes the high drug-loading capacity of liposomes and the delivery advantages of exosomes, serving as a safe and effective multi-target strategy for SSc-related skin fibrosis.