Paris polyphylla var. yunnanensis Leaf-Derived Extracellular Vesicle-Like Particles Enhance Periodontal Regeneration.

Periodontitis, a highly prevalent chronic inflammatory disease globally, faces substantial challenges in achieving periodontal tissue regeneration, necessitating the development of novel therapeutic strategies. Chinese herbal medicine-derived extracellular vesicles (CHMEVs), natural nanoscale carriers enriched with bioactive components from medicinal plants, exhibit unique therapeutic advantages in tissue repair. Here, we isolated extracellular vesicle-like particles from Paris polyphylla var. yunnanensis leaves (PP-L-EVLPs), a traditional Chinese medicinal herb native to Yunnan, and systematically evaluated their therapeutic potential for periodontal regeneration. PP-L-EVLPs were efficiently internalized by periodontal ligament stem cells (PDLSCs), enhancing their proliferation, migration, and osteogenic differentiation through up-regulation of ALP, RUNX2, and OPN. PP-L-EVLPs significantly suppressed the protein expression levels of lipopolysaccharide-induced interleukin-6 (IL-6) and IL-8 in PDLSCs. In a rat alveolar bone defect model, PP-L-EVLPs significantly promoted bone regeneration, as evidenced by micro-computed tomography, histology, and immunohistochemistry. Biosafety evaluations revealed no histopathological abnormalities or genotoxicity in major organs of Sprague-Dawley rats treated with PP-L-EVLPs. This study is the first to confirm that PP-L-EVLPs exhibit cell migration-promoting, anti-inflammatory, and osteogenic activities with excellent biosafety, offering a novel natural nano-based therapeutic strategy for periodontitis treatment.