Plant-Derived Exosome-Like Nanoparticles in Neurodegenerative Diseases: From Dual Bioactive-Delivery Roles to Translational Challenges

Yue Sun,1– 3 Zongqiang Xu,2,3 Lianhui Cui,2– 4 Jianfei Guo,2,3 Xiaohui Zhang,2,3 Yilei Xiao2,3 1School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, People’s Republic of China; 2Department of Neurosurgery, Liaocheng People’s Hospital Affiliated to Shandong First Medical University, Liaocheng, Shandong, People’s Republic of China; 3Liaocheng Key Laboratory of Brain Science and Neurological Disorders Innovation Technology, Liaocheng, Shandong, People’s Republic of China; 4Postgraduate Department, Shandong First Medical University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Xiaohui Zhang, Email zxiaohui92@163.com Yilei Xiao, Email Yileixiao@163.comAbstract: Neurodegenerative diseases, particularly Alzheimer’s disease (AD) and related disorders, remain difficult to treat because of their multifactorial pathogenesis, limited disease-modifying therapies, and insufficient central nervous system exposure of many therapeutic agents. Plant-derived exosome-like nanoparticles (PELNs) are emerging as biogenic nanovesicles that combine intrinsic bioactivity with natural nanocarrier properties. Enriched with lipids, proteins, small RNAs, and phytochemicals, PELNs may exert neuroprotective effects while offering opportunities for gastrointestinal stability, systemic transport, and potential central nervous system delivery. This review critically summarizes the dual bioactive-delivery roles of PELNs in AD and related neurodegenerative disorders. We discuss their potential mechanisms in modulating neuroinflammation, glial cell-mediated immune responses, redox imbalance, mitochondrial dysfunction, pathological protein aggregation, neural repair, and gut-brain axis regulation. We further examine how administration routes, biodistribution patterns, cellular uptake, and blood-brain barrier (BBB) models influence the interpretation of evidence for central nervous system (CNS) targeting. In addition, recent advances in isolation, purification, characterization, cargo loading, and surface engineering strategies are reviewed in the context of improving stability, targeting capacity, and translational feasibility. Despite their promise, the clinical development of PELNs remains constrained by source-dependent heterogeneity, non-standardized isolation methods, insufficiently defined critical quality attributes, inconsistent dosing metrics, limited pharmacokinetic and biodistribution data, and unresolved long-term biosafety concerns. Establishing rigorous Chemistry, Manufacturing, and Controls (CMC) frameworks, reproducible quality-control assays, and evidence-based translational pathways will be essential for advancing PELNs from experimental bioactive vesicles to clinically relevant neurotherapeutic platforms. The infographic highlights the bioactivity and nanocarrier role of PELNs (plant-derived extracellular vesicle-like nanoparticles). Their bioactivity includes antioxidant, anti-inflammatory, immunomodulatory effects and gut-brain axis regulation. As nanocarriers, they protect cargo, facilitate cellular uptake, enable cargo loading, surface engineering and interact with barriers. These functions help reduce neuroinflammation, offer antioxidant and mitochondrial protection, support neuronal survival, modulate Aβ/Tau pathology, regulate gut-brain axis and microbiota and enhance synaptic repair and plasticity. Clinical application requires scalable sources, standardized isolation, quality control, pharmacokinetics, safety, targeted engineering, manufacturing and regulatory compliance. Challenges include source variability, non-standardized isolation, undefined attributes, limited pharmacokinetics data, long-term safety concerns and regulatory issues.Infographic on PELNs’ bioactivity, nanocarrier function and clinical application process.Keywords: plant-derived exosome-like nanoparticles, PELNs, Alzheimer’s disease, AD, neurodegenerative diseases, blood-brain barrier, BBB, bioactive nanocarriers