Plant-Derived Nano and Microvesicles for Human Health and Therapeutic Potential in Nanomedicine

Abstract

Plants produce different types of nano and micro-sized vesicles. Observed for the first time in the 60s, plant nano and microvesicles (PDVs) and their biological role have been inexplicably under investigated for a long time. Proteomic and metabolomic approaches revealed that PDVs carry numerous proteins with antifungal and antimicrobial activity, as well as bioactive metabolites with high pharmaceutical interest. PDVs have also been shown to be also involved in the intercellular transfer of small non-coding RNAs such as microRNAs, suggesting fascinating mechanisms of long-distance gene regulation and horizontal transfer of regulatory RNAs and inter-kingdom communications. High loading capacity, intrinsic biological activities, biocompatibility, and easy permeabilization in cell compartments make plant-derived vesicles excellent natural or bioengineered nanotools for biomedical applications. Growing evidence indicates that PDVs may exert anti-inflammatory, anti-oxidant, and anticancer activities in different in vitro and in vivo models. In addition, clinical trials are currently in progress to test the effectiveness of plant EVs in reducing insulin resistance and in preventing side effects of chemotherapy treatments. In this review, we concisely introduce PDVs, discuss shortly their most important biological and physiological roles in plants and provide clues on the use and the bioengineering of plant nano and microvesicles to develop innovative therapeutic tools in nanomedicine, able to encompass the current drawbacks in the delivery systems in nutraceutical and pharmaceutical technology. Finally, we predict that the advent of intense research efforts on PDVs may disclose new frontiers in plant biotechnology applied to nanomedicine.

Keywords: EV biogenesis and uptake; extracellular vesicles; nanomedicine; natural products; plant-derived nano and microvesicles.

Figure 1

Isolation strategies and classification of plant-derived nano and microvesicles (PDVs). Overview of isolation methods and main types of plant vesicles (general plant-derived vesicles, apoplastic vesicles, and root-released vesicles) based on the plant source from which they derive (fruits or rhizomes, seedlings or seeds, and roots). Plant vesicles could be isolated trough differential ultracentrifugation steps and associated gradient purifications.

Figure 2

Biogenesis and secretion of plant extracellular vesicles. Plant extracellular vesicles (EVs) derive from early endosomes originated from plasma membrane by endocytosis. An early endosome becomes late endosomes and then forms multivesicular bodies which fuse with the membrane to release EVs. The alternative exocyst-mediated EVs secretion pathway described in plant is also shown.

Figure 3

Schematic representation, composition, and biological roles of plant-derived vesicles. Plant vesicles are round-shaped nano and microstructures containing a vast array of proteins, nucleic acids (mRNAs, miRNAs, and other types of short RNAs), and secondary metabolites surrounded by a lipid bilayer with membrane proteins, channels, ligands, and receptors.

Figure 4

Possible different routes of plant-derived vesicles uptake into a target cell. Recipient cells can receive plant-derived vesicles through different, well described uptake mechanisms: Phagocytosis, macropinocytosis, and clathrin-dependent endocytosis. The passive membrane fusion is also shown in the figure. The question mark indicates that this mechanisms remains still to be elucidated for PDV uptake, although described for many types of EVs.

Figure 5

Bioengineering approaches to increase efficacy of plant-derived vesicles for therapeutic purposes. Schematic representation on current strategies and possible approaches for surface-functionalization and loading of extracellular vesicles. (a) Potential receptor binding ligands may target PDVs to specific cell population. (b) Electroporation to load miRNA and siRNA in PDVs. (c) Passive loading of bioactive molecules in PDVs. N indicates the nucleus.