Source-Specific Extracellular Vesicle Functions and Engineering Strategies for Chronic Pain Management: A Comprehensive Review

Abstract: Chronic pain management faces significant limitations due to adverse effects and insufficient long-term relief from existing therapies. Extracellular vesicles (EVs) are lipid bilayer‐enclosed particles naturally carrying proteins, nucleic acids, and metabolites. Recently, EVs have emerged as a potential alternative approach. This review examines EVs from mesenchymal stem cells, neural cells, macrophages, and gut microbiota. EV activity is then assessed across the three major pain types defined by the ICD‑11: nociceptive pain, neuropathic pain, and nociplastic pain. We elucidate how source-specific EVs dynamically regulate different kinds of pain through multi-modal mechanisms, including neural signal transduction, neuroimmune axis coordination, structural neural repair, and metabolic network reprogramming. Furthermore, we discuss how these inherent therapeutic properties can be augmented through engineering approaches such as surface modification and cargo encapsulation, which enhance targeting and payload delivery. By integrating mechanistic insights into source‑specific EV functions with emerging engineering strategies, this review may provide a rational framework for developing next‑generation EV‑based analgesics. We conclude that harnessing the innate biological properties of EVs, complemented by strategic engineering, represents a potential non-opioid strategy for precise and effective management of chronic pain. Keywords: exosomes, non-opioid treatment, EV-based analgesic therapy, engineering EVs, neuroimmune modulation, neuropathic pain