Aug 2026· Bioactive Materials· Vol 67, pp. 192 - 212· 0 citations· 173 references
Medicine
TL;DR
A pathology-driven and engineering-guided perspective for understanding the rational design and future development of exosome-based therapeutics for CNS disorders is provided.
Abstract
The blood–brain barrier (BBB) remains a major biological obstacle limiting the effective delivery of therapeutics for central nervous system (CNS) disorders. Although conventional drug delivery approaches have achieved continuous advances, their clinical translation is frequently restricted by limited brain penetration, insufficient target specificity, and systemic adverse effects. Exosomes, endogenous extracellular vesicles (EVs) involved in intercellular communication, have emerged as promising candidates for CNS therapeutic delivery owing to their favorable biocompatibility, relatively low immunogenicity, and potential ability to interact with biological barriers. In this review, we first summarize the structural characteristics of the BBB and the mechanisms underlying exosome–BBB interactions and transport. We then discuss current strategies for exosome isolation, characterization, and engineering, highlighting how these approaches influence therapeutic performance and translational feasibility. Subsequently, we analyze recent advances in exosome-based therapies for major CNS disorders, including neurodegenerative diseases, brain tumors, and ischemic stroke, with emphasis on how distinct pathological environments guide the design of exosome cargos, targeting strategies, and functional modifications. Finally, we discuss key challenges associated with clinical translation, including manufacturing standardization, pharmacokinetic evaluation, safety assessment, and regulatory considerations. This review provides a pathology-driven and engineering-guided perspective for understanding the rational design and future development of exosome-based therapeutics for CNS disorders.
This review highlights recent advances in exosome biology, cargo-sorting mechanisms, and engineering strategies designed to enhance therapeutic delivery and targeting within the central nervous system and discusses how exosomes compare with conventional delivery platforms and critically examine the major barriers limiting their clinical translation.
Central nervous system (CNS) inflammation and brain tumor treatment are constrained by the heterogeneity of the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB), as well as by the sequential barriers to drug delivery across lesions, target cells and subcellular organelles. Simply increasing brain exposure does not ensure that drugs reach their actual sites of action. This review systematically examines the pathological roles and therapeutic rationales of mitochondrial, lysosomal, nuclear, endoplasmic reticulum and Golgi apparatus dysfunction in neuroinflammation and glioblastoma within a two-stage delivery framework encompassing barrier crossing, lesion accumulation, cellular uptake and subcellular organelle localization. It also summarizes key design considerations for liposomes, polymeric nanoparticles, biomimetic membrane-based carriers, exosome-like carriers and focused ultrasound-assisted delivery strategies. Furthermore, translational bottlenecks are discussed, including BBB/BBTB heterogeneity, endosomal/lysosomal escape, organelle off-targeting, long-term safety and the extrapolation of preclinical models. Finally, personalized delivery designs guided by cascade targeting, dynamic visualization-based validation and disease stratification are proposed to support precise treatment of CNS inflammation and brain tumors.
Man-Ru Zhang, Bo-Han Chen, Tie-Zheng Li et al.· Pharmaceutics· 0 citations
Drug delivery systems based on nanoparticles have emerged as promising approaches for overcoming the blood–brain barrier (BBB), a major obstacle to treating disorders of the central nervous system (CNS). There are several reasons why conventional therapies fail, including poor brain penetration, rapid drug clearance, and nonspecific distribution. This review critically evaluates recent advances in nanoparticle-mediated BBB targeting, focusing particularly on in vivo findings. As part of this review, lipid-based, polymeric, metallic, dendrimeric, exosome-inspired, and magnetic nanoparticles are discussed in conjunction with their transport mechanisms. The review compares their therapeutic efficacy, biodistribution, targeting ability, and safety across a variety of neurological conditions. Additionally, emerging technologies are discussed, including biomimetic nanoparticles, stimuli-responsive systems, artificial intelligence, and personalized nanomedicine. Additionally, this review critically discusses the major barriers to clinical translation, including biosafety, manufacturing, and regulatory challenges. As a result, this review provides an updated perspective on current progress and future prospects for developing effective brain-targeted nanomedicine.
A. Al-allaq, H. A. Hassan, Hidayet Hi̇dayet et al.· Micro· 0 citations
Alzheimer’s disease (AD), a progressive neurodegenerative disorder, remains a major global health challenge owing to its complex pathogenesis and the presence of the blood-brain barrier (BBB), which substantially limits the delivery of effective therapeutics to the brain. Extracellular vesicles (EVs), which exhibit favorable biocompatibility, low immunogenicity, and an intrinsic capacity to cross the BBB, have emerged as promising therapeutic agents and delivery platforms for AD. This review focuses on the therapeutic potential of EV-based interventions in AD and summarizes recent advances in EV-mediated modulation of AD-related pathological processes, including amyloid-β (Aβ) clearance, tau protein regulation, neuroinflammation suppression, oxidative stress attenuation, and synaptic repair. Although EV-based therapies offer notable advantages, such as targeted BBB penetration and reduced immunogenic responses, their clinical translation remains constrained by safety concerns, including off-target effects, dose-dependent toxicity, and potential disturbances in neuroplasticity. In addition, this review discusses EV engineering strategies aimed at regulating the gut-brain axis (GBA), enhancing brain targeting, and advancing clinical translation. EV-based therapeutic interventions should therefore be developed within a safety-oriented framework supported by rigorous short- and long-term toxicological evaluation. Overall, this review highlights the therapeutic promise of EVs for AD while underscoring the need for rational engineering, standardized characterization, and safety-centered translational strategies to ensure clinical feasibility.
Ailin Wu, Yan Zeng, Yilin Huang et al.· Extracellular Vesicles and C...· 0 citations
The findings support the therapeutic potential of exosome-based platforms while also highlighting major challenges, including inconsistencies in isolation protocols, limited cargo- loading capacity, targeting specificity, and in vivo stability.
Shatrudhan Prajapati, Shikha Yadav· Current Neurovascular Resear...· 0 citations
Alzheimer’s disease (AD) remains a major neurodegenerative disorder lacking effective long-term disease-modifying therapies. Current pharmacological approaches provide primarily symptomatic benefit, while recently approved anti-amyloid monoclonal antibodies offer only modest clinical efficacy and are constrained by safety concerns, high costs, and limited blood–brain barrier (BBB) penetration. In this context, exosome-based strategies have emerged as potential therapeutic platforms in AD research. As endogenous nanovesicles, exosomes exhibit favorable biocompatibility, intrinsic BBB-crossing capacity, and the ability to deliver diverse therapeutic cargo across multiple pathological pathways. Through bioengineering approaches, exosomes may additionally be optimized for targeted brain delivery and therapeutic personalization. Nevertheless, despite their conceptual and preclinical advantages, exosome-based therapies remain at an early translational stage, with unresolved challenges related to large-scale production, standardization, biodistribution, and long-term safety. This review provides a comparative translational analysis of conventional and exosome-based therapeutic strategies in AD, focusing on mechanistic targeting, delivery efficiency, safety and tolerability, therapeutic personalization, and translational readiness. We critically evaluate the extent to which exosome-based platforms may address the limitations of current therapies while highlighting the key barriers that continue to limit their clinical translation and real-world applicability.
E. Andreadou, Evangelia Evangelopoulou, Magdalini Tsolaki et al.· Current Issues in Molecular...· 1 citation
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