Characteristics of Extracellular Vesicles and Preclinical Testing Considerations Prior to Clinical Applications

Abstract

Cell therapy products have significant limitations, such as storage instability, difficulties with transportation, and toxicity issues such as tumorigenicity and immunogenicity. Extracellular vesicles (EVs) secreted from cells show potential for therapeutic agent development. EVs have not been widely examined as investigational drugs, and non-clinical studies for the clinical approval of EV therapeutic agents are challenging. EVs contain various materials, such as DNA, cellular RNA, cytokines, chemokines, and microRNAs, but do not proliferate or divide like cells, thus avoiding safety concerns related to tumorigenicity. However, the constituents of EVs may induce the proliferation of normal cells; therefore, the suitability of vesicles should be verified through non-clinical safety evaluations. In this review, the findings of non-clinical studies on EVs are summarized. We describe non-clinical toxicity studies of EVs, which should be useful for researchers who aim to develop these vesicles into therapeutic agents. A new method for evaluating the immunotoxicity and tumorigenicity of EVs should also be developed.

Lipidic Nanoparticles, Extracellular Vesicles and Hybrid Platforms as Advanced Medicinal Products: Future Therapeutic Prospects for Neurodegenerative Diseases

“…Firstly, due to their natural origin, EVs seem to have a more biocompatible profile [ 77 , 78 ]. Nevertheless, the diverse sources of EVs necessitate specific preclinical tests on each occasion to assess their immunogenicity [ 79 ]. Moreover, the complex mixture of molecules within EVs target different biochemical pathways, resulting in a synergistic therapeutic effect, more efficient than that produced by individual factors [ 61 ].…”

Extracellular Vesicles in Pathophysiology: A Prudent Target That Requires Careful Consideration

“…Similarly, while many pre-clinical studies indicate that the administration of EVs is likely to exhibit low immunogenicity, others imply that more comprehensive assessments that narrate the varieties in the cell-type-specific cargo of EVs are required [220,221]. EVs carry a host of immunoregulatory molecules on their surface, and therefore serve as potent modulators of immune activity [222].…”

From Theory to Therapy: The Advancements of Extracellular Vesicles in Immunotherapy

“…As such, they are inherently biocompatible and less likely to trigger adverse immune responses or cytotoxic effects after fusion compared to synthetic delivery vehicles. [52,75] The fusion of EVs with recipient cells is a relatively nontoxic process, making it an attractive mechanism for therapeutic delivery in immunotherapy, e.g., for intracellular delivery of transcription factors and microRNA (miRNA)based regulatory elements for immune cell reprogramming and modulation of tolerance. [76] In summary, EVs theoretically present ideal starting conditions for immunotherapeutic strategies.…”