Neurodegenerative disorders—including Alzheimer's disease (AD), Parkinson's disease (PD), and Multiple Sclerosis (MS)—represent an expanding global health challenge. These conditions substantially reduce quality of life by impairing cognition, mood, behavior, and motor function and account for large numbers of disability-adjusted life years (DALYs) worldwide. Current pharmacotherapies, especially small-molecule agents, are constrained by limited central nervous system (CNS) bioavailability due to the blood-brain barrier (BBB), systemic adverse effects, and adherence issues. These limitations have driven interest in novel delivery platforms capable of targeted CNS transport and reduced peripheral exposure.
Exosomes are endogenous nanoscale extracellular vesicles, typically 30–150 nm in diameter, produced by many cell types including mesenchymal stem cells, neural stem cells, and immune cells. Their biogenic origin confers several favorable features for CNS drug delivery: low immunogenicity, inherent biocompatibility, and the ability to carry diverse cargoes such as proteins, messenger RNA (mRNA), and microRNA (miRNA). Exosomes’ natural capacity to interact with recipient cells and to cross the BBB positions them as promising carriers for targeted brain delivery and as potential alternatives to synthetic nanocarriers like liposomes, niosomes, and solid lipid nanoparticles.
The review provides an overview of methods used to classify, isolate, and characterize exosomes, and summarizes strategies to load therapeutic payloads. Isolation and characterization aim to yield reproducible vesicle populations with defined physical and biochemical attributes. Drug-loading approaches can be designed to incorporate small molecules, nucleic acids, or proteins into exosome cargo either during biogenesis or via post-isolation manipulation. These capabilities underpin exosomes’ versatility as delivery vectors for disease-modifying therapeutics targeted to neurodegenerative disorders.
Multiple routes for delivering exosome-based therapeutics to the CNS are discussed and compared. These include:
Each route presents trade-offs between invasiveness, target specificity, systemic exposure, and feasibility for repeated dosing.
The review places particular emphasis on the intranasal route. Intranasal administration exploits direct nose-to-brain pathways via the olfactory and trigeminal nerves, enabling agents to bypass the BBB and potentially reach the CNS with reduced systemic distribution. As a noninvasive approach, intranasal delivery can facilitate repeat dosing and improve patient acceptability compared with invasive techniques. The authors highlight intranasal delivery as an especially attractive option for clinical translation of exosome therapeutics, given its potential to combine effective CNS targeting with lower peripheral adverse effects.
Exosomes are discussed as having dual influences on BBB biology. On one hand, engineered or naturally derived exosomes may therapeutically modulate BBB transport to promote delivery of beneficial cargo into the CNS. On the other hand, exosomes can also participate in pathological processes that affect BBB integrity or contribute to disease propagation, underscoring the need to understand context-specific exosome effects when designing therapies.
The review surveys preclinical and early clinical data supporting exosome-based approaches in AD, PD, and MS. Across these neurodegenerative conditions, exosomes have been explored as carriers of neuroprotective molecules, nucleic acid therapeutics, and disease-modifying cargos. While preclinical results indicate promise—and early clinical investigations are beginning to emerge—the abstract notes that detailed outcomes, study designs, and specific clinical results are not reported there. Thus, while evidence is encouraging, it remains preliminary and requires larger controlled clinical trials to establish efficacy and safety.
Significant translational hurdles must be addressed before exosome-based intranasal therapies can reach regulatory approval. Key challenges identified include:
The review emphasizes that resolving these manufacturing and regulatory issues is essential for moving exosomal candidates from promising preclinical agents to approved treatments for neurodegenerative disorders.
Exosomes combine biological compatibility, cargo versatility, and a natural capacity to access the CNS, making them compelling drug carriers for neurodegenerative diseases. The intranasal route offers a noninvasive nose-to-brain pathway that can bypass the BBB and reduce systemic exposure, positioning it as a key translational strategy. However, the field faces practical barriers in GMP-scale manufacture, dosing standardization, regulatory alignment, and the need for large placebo-controlled trials. Until those challenges are met and clinical efficacy is demonstrated in robust studies, intranasal exosome therapeutics remain promising but investigational. The authors report no competing interests and indicate no specific grant funding for the review.