Plant Extracellular Vesicle-Encapsulated Phytometabolites for Reversing Cellular Senescence Associated with Chronic Kidney Disease: A Mechanistic Review and Research Roadmap

Abstract

CKD is characterized by the presence of senescent tubular epithelial cells in increasing numbers in association with the injury of the nephrons, and the secretory phenotypes associated with these senescent cells are responsible for the fibrosis seen during CKD progression. Natural small molecule senotherapy agents (senolytics and senomorphics) obtained from plant sources like quercetin, fisetin, and curcumin have demonstrated biological activity towards senescent cells, and one senolytic combination drug has even been used in a clinical trial in diabetic kidney disease patients. Despite the biological activity of these drugs, they lack aqueous solubility, fast systemic clearance, and renal bioavailability as free molecules. Extracellular vesicles from edible plants such as ginger, grape, and grapefruit – plant-derived extracellular vesicles (PEVs) – have been proposed as another delivery vehicle for senotherapeutic drugs, providing natural biological activity, good biocompatibility, low manufacturing cost, and ability to load phytometabolite drugs like curcumin. This review summarizes the physiology of cellular senescence in CKD, the evidence for plant-based compounds as senotherapeutic agents, and the rationale behind using PEVs to deliver the drugs. Three areas of literature that have so far been studied largely in isolation are brought together to construct a five-point hypothesis about how PEV-encapsulated plant metabolites can mitigate renal cellular senescence. The review ends with a proposed step-by-step approach to translating the hypothesis into in vitro and animal studies before human trials. There is no experimental data provided here; each proposed link in the mechanistic chain is a hypothesis formed based on indirect evidence.