Extracellular vesicle-based drug overview: research landscape, quality control and nonclinical evaluation strategies

Abstract

Extracellular vesicles share lipid‒protein membranes with their parent cells, allowing for the targeted transfer of bioactive cargo to recipient cells for functional modulation. The biological features allow extracellular vesicles to serve both as intrinsic therapeutics and as engineered delivery vehicles for targeted molecule transport. In recent years, extracellular vesicle-based therapy has shown great potential as a new therapeutic approach for traumatic conditions and degenerative, acute, and refractory diseases. As extracellular vesicle engineering continues to evolve, more innovative drugs are expected to receive investigational new drug approvals and marketing approvals from regulatory agencies in the future. However, many challenges exist in terms of mechanistic understanding, engineering modifications, manufacturing processes, quality control, and nonclinical research, and no drug regulatory authorities have currently issued specific technical evaluation guidelines for extracellular vesicle-based drugs, all of which have hindered the clinical translation of these drugs. In this article, which is focused primarily on extracellular vesicles derived from mammalian cells, we summarize the clinical translation and process development research status of extracellular vesicle-based drugs and propose both general considerations and key aspects of quality control strategies and nonclinical evaluations in the development process. The aim of this review is to provide valuable references for the development and evaluation of extracellular vesicle-based products, accelerate the clinical translation process, and benefit patients as soon as possible.

Fig. 1

Key milestones in the development of extracellular vesicle (EV)-based drugs. The figure displays a chronological timeline highlighting significant milestones or events in EV drug development from 1946 to 2023. Each marked year represents a pivotal development. (IND investigational new drug, ARDS acute respiratory distress syndrome, RMAT regenerative medicine advanced therapy)

Fig. 2

Therapeutic applications of extracellular vesicles from various systems in treating diseases. The figure summarizes the diverse clinical applications of extracellular vesicle-based therapies, organized by administration routes, target diseases, and mechanistic effects. The dashed lines indicate the administration routes and the mechanistic effects of the target disease. The representative schematics in this figure were created with BioRender.com

Fig. 3

Statistical analysis of the disease type, extracellular vesicle (EV) source, and sponsor country of the 117 interventional studies. a The disease type was categorized into inflammatory (e.g., osteoarthritis, Crohn’s disease, ulcerative colitis, inflammatory bowel disease), pulmonary (e.g., COVID-19, acute respiratory distress syndrome, bronchopulmonary dysplasia), skin (e.g., burns, wounds, androgenetic alopecia, fistula perianal), nervous system (e.g., ischemic stroke, Alzheimer disease), cancer (e.g., lung cancer, colon cancer, lymphoma), and other diseases (e.g., premature ovarian failure, myocardial infarction). b The EV sources used in the studies were categorized. Other stem cells represent stem cells that are not mesenchymal stem cells, such as induced pluripotent stem cells and limbal stem cells. The blood source included blood cells and plasma. Others are sources that are not included in the categorized sources. c The sponsor countries of the studies were analyzed. The values represent the number of studies and are shown in Arabic numerals

Fig. 4

Key aspects of nonclinical studies of extracellular vesicle (EV) drugs. The key concerns regarding the representativeness of samples, animal species/models, and routes of administration are introduced for developing a nonclinical study strategy for EV-based drugs. The critical aspects of pharmacokinetics, pharmacodynamics, and safety evaluations in nonclinical assessments of EV drugs are outlined. The representative schematics in this figure were created with BioRender.com