Plant-derived extracellular vesicles as potential smart nano drug delivery systems for antioxidant vitamins C and E in Alzheimer's disease

The prevalence of Alzheimer's disease is increasing as the aging population and life expectancy increase. This calls for the development of effective therapeutics with fewer side effects that can manage the progression of the disease. Over the years, the only approved drugs for AD include donepezil, galantamine, memantine, and rivastigmine. Unfortunately, these treatments do not cure AD but rather alleviate symptoms of AD. Their long-term safety is not clear leaving room for the search for more therapies that would effectively prevent and manage the progression of AD. For this reason, antioxidants have been employed to target oxidative stress (OS) in AD. Oxidative stress contributes greatly to the progression of AD by increasing the accumulation of amyloid-beta, hyper-phosphorylated tau proteins forming neurofibrillary tangles, and mitochondria dysfunction. With endogenous antioxidants being overwhelmed leading to OS, exogenous antioxidants could be therapeutic options for AD. Studies conducted utilizing antioxidant vitamins C and E have been revealed to reduce cognitive impairment in animal models of AD. However, clinical trials have produced inconclusive results. One plausible explanation for the disparity is the bioavailability of these antioxidant vitamins in the brains of AD patients. Plant-derived extracellular vesicles (PDEVs) are novel nano-delivery systems for targeted delivery of therapeutics. Hence, this review highlights the potential of PDEVs as delivery vehicles to increase the bioavailability of these antioxidant vitamins in the brain. The study emphasizes the role of oxidative stress in the pathobiology of AD and the therapeutic benefits of antioxidants. We provide an insight into isolation protocols, loading strategies, and bioengineering of PDEVs for targeted delivery of vitamins C and E. Challenges and future perspectives of these nanovesicles as platforms for drug delivery to the brain tissue are also discussed. We are optimistic that more research in this line could be explored to tackle the challenges of failed clinical trials of these vitamins as therapeutics for AD. [Display omitted] •Plants are rich sources for large-scale production of ready-to-use extracellular vesicles (EVs) for drug delivery.•Plant-derived EVs contain inherent cargoes that possess therapeutic benefits for Alzheimer's disease.•Encapsulation of vitamins C and E into EVs can increase the bioavailability in the brain.•Decoration of EVs with small molecules through