<i>Perilla frutescens</i> Leaf-Derived Extracellular Vesicle-Like Particles Carry Pab-miR-396a-5p to Alleviate Psoriasis by Modulating IL-17 Signaling

Psoriasis, a chronic inflammatory skin disorder, remains challenging to treat due to poor skin barrier penetration, limited efficacy, and adverse effects of current therapies. Natural plant-derived extracellular vesicle-like particles (EVPs) have emerged as biocompatible carriers for bioactive molecules. Among various medicinal plants screened, <i>Perilla frutescens</i> leaf-derived EVPs (PLEVPs) exhibited strong anti-inflammatory and antioxidant effects. By incorporating PLEVPs into a hydrogel formulation, we enhanced their stability, retention at psoriatic lesions, and transdermal delivery efficiency. In vivo studies demonstrated that the PLEVPs markedly alleviated psoriasis symptoms in both preventive and therapeutic mouse models, outperforming conventional treatments. This effect was attributed to reduced oxidative stress, modulation of Treg cells, and promotion of keratinocyte apoptosis. Transcriptomic analysis revealed enrichment of the interleukin-17 (IL-17) signaling pathway, a major driver of psoriasis, while small RNA sequencing identified pab-miR396a-5p, an endogenous microRNA (miRNA) within PLEVPs, as a key regulator. Mechanistic studies showed that pab-miR396a-5p targets the 3'-untranslated region of plant heat shock protein 83a, a homolog of mammalian heat shock protein 90, leading to the suppression of nuclear factor-kappa B and Janus kinase/signal transducers and activators of transcription signaling, inhibiting the IL-17 signaling pathway. Validation using lipid nanoparticles encapsulating pab-miR396a-5p mimics confirmed comparable therapeutic effects. This study highlights the potential of plant-derived EVPs as carriers of endogenous miRNAs, enabling interkingdom communication and offering a scalable platform for psoriasis therapy.