Plant Nanovesicles Emerge as Natural Healers for Aging and Tissue Damage

As global populations age, demand is growing for safe, scalable therapies that address tissue damage and aging biology simultaneously. Mammalian extracellular vesicles (EVs) have shown therapeutic promise but are expensive to produce, difficult to scale, and carry biosafety concerns. Plant-derived nanovesicles (PDNVs) — membrane-enclosed nanoparticles naturally secreted by plant cells — offer a compelling alternative with abundant, sustainable raw material sources and excellent safety profiles.

PDNVs are generated through three biogenesis pathways: the multivesicular bodies (MVB) pathway (considered primary), the vacuoles pathway (important in immune defense), and the extracellular positive organelle (EXPO) pathway first identified in Arabidopsis and tobacco. Their cargo is remarkably diverse: heat shock proteins (HSPs) such as HSPA8 support stress response and tissue repair; aquaporins (AQP3, AQP4) regulate hydration and skin barrier function; lipids including phosphatidic acid (PA), phosphatidylcholine (PC), and phosphatidylethanolamine (PE) drive membrane bioactivity; and small RNAs — particularly miRNAs — cross species barriers to regulate host gene expression. For example, ginger PDNV miR168a-5p targets SIRT1 pathways, while tea-derived vesicles deliver miRNAs that modulate inflammation.

Isolation methods reviewed include differential ultracentrifugation (UC), sucrose density gradient centrifugation (SDGC), ultrafiltration (UF), and commercial kits. PDNVs from diverse sources — herbs, fruits, vegetables, seeds, leaves, flowers, roots, bark, tea leaves, and mushrooms — typically range from 75 to 210 nm in diameter with negative zeta potentials ensuring colloidal stability. Their therapeutic applications span multiple organ systems: ginseng PDNVs restore endothelial function to accelerate diabetic wound healing; cRGD-modified mulberry leaf PDNVs deliver urokinase plasminogen activator (uPA) to resolve venous thromboembolism; ginger PDNVs reduce intestinal inflammation and protect against colitis; berry-derived vesicles activate Nrf2 antioxidant pathways to counteract cellular senescence; and Panax notoginseng PDNVs promote osteogenesis for bone repair.

For antiaging specifically, PDNVs act through multiple complementary mechanisms: reducing ROS and oxidative stress, inhibiting NLRP3 inflammasome activation to dampen inflammaging, activating AMPK/mTOR and Nrf2 pathways, modulating telomerase activity, and promoting mitophagy to clear damaged organelles. Skin aging applications are particularly advanced, with topical PDNVs from aloe vera, grape, and bitter melon demonstrating collagen synthesis promotion, melanin suppression, and UV damage repair in preclinical models.

Despite significant promise, the field faces critical challenges: lack of standardized isolation and characterization protocols, incomplete understanding of cross-species RNA delivery mechanisms, limited large-scale production methods, insufficient clinical trial data, and regulatory uncertainty. The authors propose five strategic priorities: standardizing production and quality control, elucidating molecular mechanisms via omics approaches, engineering surface modifications for targeted delivery, conducting rigorous clinical trials, and developing scalable green manufacturing platforms.