Navigating the Global Regulatory Landscape for Exosome-Based Therapeutics: Challenges, Strategies, and Future Directions

Abstract

Extracellular vesicle (EV)-based therapies have attracted considerable attention as a novel class of biologics with broad clinical potential. However, their clinical translation is impeded by the fragmented and rapidly evolving regulatory landscape, with significant disparities between the United States, European Union, and key Asian jurisdictions. In this review, we systematically analyze regional guidelines and strategic frameworks governing EV therapeutics, emphasizing critical hurdles in quality control, safety evaluation, and efficacy demonstration. We further explore the implications of EVs' heterogeneity on product characterization and the emerging direct-to-consumer market for EVs and secretome preparations. Drawing on these insights, in this review, we aim to provide a roadmap for harmonizing regulatory requirements, advancing standardized analytical approaches, and fostering ongoing collaboration among regulatory authorities, industry stakeholders, and academic investigators. Such coordinated efforts are essential to safeguard patient welfare, ensure product consistency, and accelerate the responsible integration of EV-based interventions into clinical practice.

Keywords: clinical translation; exosomes; extracellular vesicles; global regulatory harmonization; manufacturing scalability; quality control; regulatory framework; standardization; therapeutics.

Figure 1

Comparative overview of the principal advantages and key challenges in exosome-based therapeutics. (Left Panel): core advantages—efficient barrier crossing, high biocompatibility and low immunogenicity, versatile cargo loading, targeted delivery, and improved stability. (Right Panel): main hurdles—regulatory ambiguity, mechanistic gaps, scale-up and purification constraints, quality control issues, and batch heterogeneity.

Figure 2

The proportion of EV-based clinical trials registered in the WHO ICTRP by regulatory jurisdiction. China-NMPA accounts for 61% of total registrations, followed by the U.S.A.’s FDA (17%), Japan’s PMDA (7%), India’s CDSCO (4%), South Korea’s MFDS, Australia’s TGA, and the United Kingdom (3% each), with smaller shares from the EU’s EMA (CTIS) (1%), Taiwan’s TFDA (1%), and Switzerland’s Swissmedic (<1%).

Figure 3

Global regulatory ecosystem for EV-based therapeutics. Centralized ICH-driven harmonization through ISEV/MISEV guidelines informs regional frameworks, guiding content characterization and safety assessment. Divergent country-specific pathways—USA (FDA), EU (EMA), South Korea (MFDS), Japan (PMDA), India (CDSCO/ICMR), Taiwan (TFDA), China (NMPA), UK (MHRA), Switzerland (Swissmedic)—are mapped alongside regulatory classifications (e.g., biologics, ATMPs) and approval processes. This schematic underscores the complexity and the need for unified standards.