# Plant Exosomal Vesicles: Perspective Information Nanocarriers in Biomedicine
## 9 Routes of Exosome Administration  
Plant nanovesicles have a number of advantages in the delivery of substances in comparison with existing analogues. Firstly, their small size, negative charge, affinity for the plasma membrane, and pronounced physicochemical stability at various pH values and temperatures allow the nanovesicles to penetrate effectively the target cells. At the same time, the phospholipid bilayer protects the content of nanovesicles from enzymatic degradation by proteinases and nucleases. Secondly, the nanovesicles have a high potential for targeted delivery of therapeutic agents, which reduces the probability of adverse reactions in clinical use. Thirdly, the nanovesicles successfully diffuse through the blood-brain barrier (BBB), avoiding an inflammatory response, unlike artificially made liposomes and animal exosomes [82]. Currently, the main obstacles for the use of plant nanovesicles are insufficient standardization levels of respective technologies and limited practical experience. Particularly, there is no universally recommended isolation protocol to date, while the existing ones still have their own drawbacks, such as high cost, the possibility of introducing contaminants, and the instability of exosomes during processing [103]. There is still a need for further development of the methods for precise quantification of the molecular and biochemical parameters of exosomes. The main disadvantage for promoting exosomes as therapeutics is the lack of a way to obtain a drug with a single potency, or at least containing a specific set of bioactive molecules. Effective technologies for obtaining exosomes in the amounts sufficient for a therapeutic application on humans are yet to be developed. Furthermore, the lack of a clear regulatory procedure (EMA/FDA) that is needed to move research into the production and commercialization phases, presents certain barriers to the development of exosome-based therapies. Nevertheless, there are four main ways of introducing nanovesicles into the body at present, namely oral, transdermal, intranasal, and intravenous. The choice of a specific method depends on the purpose of therapy and the administered substance, as well as the target organ of the patient. Oral administration is the simplest method in comparison with others. When nanovesicles are not cleaved by food enzymes, they can be preserved in the recipient's body for a long time. This method is preferred for the targeted therapy of the stomach, colon, upper ileum, and liver [104]. However, the surface properties of exosomes, particularly their membrane proteins, could be partially altered by interactions with other substances in the digestive tract [105]. Moreover, it is difficult to select the exact dose of the drug, since oral absorption is variable and incomplete. The oral route of administration is not applicable in emergency situations because the process of absorption is time consuming and the patient must be able and compliant to take the drug. The transdermal method is used primarily for delivery to the skin and circulatory system. There are two routes of nanovesicle penetration during transdermal application: using physical channels of the skin with a sufficient micrometer diameter to pass to the vessels and through the stratum corneum. It is assumed that after applying nanovesicles to the skin, they penetrate through the surface of lipid-rich channels on the hair follicles. These nanovesicles can reach the hair shafts by entering the hair matrix cells and moving further by cell differentiation or by the direct penetration into the hair shafts from the hair tip. Another method of penetration into the dermis is through the stratum corneum. Nanovesicles are able to penetrate the skin through trans-follicular pathways, since their surface has a bilayer flexible structure [106]. Formulations for the transdermal route should avoid the risk of irritation and inflammation.