Brainstem Correlates of Tinnitus and Hyperacusis in Normal-Hearing Listeners: Distinct Neural Signatures Linked to Cochlear Nerve Degeneration.

Central nervous system (CNS) disorders remain one of the most intractable global health burdens, featuring high morbidity, intricate pathophysiological mechanisms, and substantial clinical bottlenecks in therapeutic intervention [,]. Representative pathological conditions, including intracranial tumors, ischemic stroke (IS), Alzheimer's disease (AD), and Parkinson's disease (PD), impose enormous socioeconomic and healthcare burdens on affected individuals and public health systems across the globe [,]. Effective treatment of CNS diseases, particularly the precise and efficient delivery of therapeutics to the affected brain regions, is critically hampered by the blood–brain barrier (BBB)—a highly selective semipermeable border that shields the brain from systemic circulation [,]. Structurally, the BBB is constituted by brain microvascular endothelial cells (BMECs), pericytes, astrocytes and the basement membrane, and leverages tight junctions (TJs), multiple efflux transporters and metabolic enzymes to rigorously restrict the transmembrane penetration of exogenous molecules into the CNS []. Consequently, most small-molecule drugs and nearly all macromolecular therapeutics, including monoclonal antibodies and recombinant proteins, exhibit limited BBB permeability, substantially restricting their therapeutic efficacy in CNS disorders []. Such inherent biological barrier limitations have urgently propelled the innovation and development of advanced brain-targeted delivery strategies, with the core goal of optimizing in vivo pharmacokinetic distribution and enhancing the enrichment efficiency of therapeutic payloads in lesion brain tissues. Given the inherent limitations and unsatisfactory efficacy of conventional drug delivery systems, biomimetic nanomedicine has emerged as a breakthrough direction for overcoming CNS delivery dilemmas. Exosomes, a class of nanoscale extracellular vesicles (EVs) derived from endosomal pathways, have emerged as promising candidates for CNS therapeutic delivery due to their unique biological properties [, , ]. As vital intercellular communication mediators, these natural nanostructures are capable of encapsulating and transporting diverse bioactive cargoes encompassing proteins, lipids and nucleic acids, thereby participating in the regulation of physiological homeostasis and the progression of multiple pathological processes []. The unique biological profile of exosomes, characterized by their high biocompatibility, low immunogenicity, extended circulatory stability, and potential ability to interact with and traverse biological barriers, positions them as highly promising candidates for targeted therapeutic delivery to the CNS [, , ]. Notably, beyond functioning as passive carriers, exosomes derived from specific cell types can also exert intrinsic biological activities, including neuroprotection, immunomodulation, regulation of neurogenesis, and restoration of tissue homeostasis. Existing literature on exosome-based therapies for brain disorders has mainly focused on specific disease contexts, individual engineering strategies, or particular aspects of exosome biology and delivery mechanisms [,]. Although these studies have advanced the field, the relationships among disease pathology, therapeutic objectives, and exosome engineering choices have not been systematically compared. AD, PD, glioblastoma (GBM), and IS differ in their dominant pathological processes, target-cell populations, and therapeutic contexts. These differences may help explain variations in the design and application of current exosome-based therapeutic strategies. This review first summarizes the biological basis of exosome–BBB interactions, including BBB organization, disease-associated barrier alterations, and the evidence supporting different endothelial uptake and transport processes. We then examine current approaches to exosome isolation, purification, characterization, and engineering, with emphasis on their effects on product quality, functional consistency, and translational feasibility. Subsequent sections discuss exosome-based strategies in AD, PD, GBM, and IS and compare how disease-associated pathological features are reflected in current engineering priorities. Finally, we evaluate major translational challenges, including manufacturing standardization, pharmacokinetic assessment, safety evaluation, and regulatory considerations (). By integrating pathological context with engineering and translational considerations, this review provides a comparative perspective on the design and development of exosome-based therapeutics for CNS disorders.