Exosomes: the next-generation therapeutic platform for ischemic stroke

Abstract

Current therapeutic strategies for ischemic stroke fall short of the desired objective of neurological functional recovery. Therefore, there is an urgent need to develop new methods for the treatment of this condition. Exosomes are natural cell-derived vesicles that mediate signal transduction between cells under physiological and pathological conditions. They have low immunogenicity, good stability, high delivery efficiency, and the ability to cross the blood-brain barrier. These physiological properties of exosomes have the potential to lead to new breakthroughs in the treatment of ischemic stroke. The rapid development of nanotechnology has advanced the application of engineered exosomes, which can effectively improve targeting ability, enhance therapeutic efficacy, and minimize the dosages needed. Advances in technology have also driven clinical translational research on exosomes. In this review, we describe the therapeutic effects of exosomes and their positive roles in current treatment strategies for ischemic stroke, including their anti-inflammation, anti-apoptosis, autophagy-regulation, angiogenesis, neurogenesis, and glial scar formation reduction effects. However, it is worth noting that, despite their significant therapeutic potential, there remains a dearth of standardized characterization methods and efficient isolation techniques capable of producing highly purified exosomes. Future optimization strategies should prioritize the exploration of suitable isolation techniques and the establishment of unified workflows to effectively harness exosomes for diagnostic or therapeutic applications in ischemic stroke. Ultimately, our review aims to summarize our understanding of exosome-based treatment prospects in ischemic stroke and foster innovative ideas for the development of exosome-based therapies.

Figure 1

Timeline of literature sources associated with exosomes and ischemic stroke. Exosomes, first discovered in 1983, have emerged as crucial mediators of intercellular communication. Their potential therapeutic effects on IS have been extensively studied in recent years. These effects include anti-inflammatory, anti-apoptotic, autophagy regulatory, angiogenic, neurogenic, and glial scar formation reduction activities. Researchers have investigated various therapeutic strategies, including exercise (Wang et al., 2020b), RIC (Xiao et al., 2017), and EA (Zhang et al., 2020a). These methods aim to stimulate the release of exosomes and thereby exert neuroprotective effects. As our understanding of exosomes deepens, they have been increasingly engineered for drug delivery purposes. For instance, the integration of edaravone with exosomes was reported in 2020, followed by tPA in 2023. Additionally, Hu et al. (2021) introduced an innovative exosome-eluting stent that offers a promising new avenue for IS therapy. Created with Microsoft PowerPoint 2021. EA: Electroacupuncture; RIC: remote ischemic conditioning; tPA: tissue plasminogen activator.

Figure 2

The pathological mechanism of ischemic stroke. Ischemia and hypoxia induce mitochondrial dysfunction, calcium overload, ROS production, excitatory neurotransmitter generation, and inflammatory cell infiltration, which lead to brain cell apoptosis and death. Upward arrows indicate an increase, and downward arrows indicate a decrease. Created with Microsoft PowerPoint 2021. BBB: Blood–brain barrier; CAM: cell adhesion molecules; ROS: reactive oxygen species.

Figure 3

The neuroprotective mechanisms of exosomes after ischemic stroke. Exosomes have key anti-inflammation, anti-apoptosis, autophagy-regulation, angiogenesis, neurogenesis, and glial scar formation reduction effects via direct or indirect communication with cells in the ischemic area and contribute to functional recovery after stroke. Created with Microsoft PowerPoint 2021.

Figure 4

Role of exosomes in exercise, remote ischemic conditioning, and electroacupuncture. Exercise, remote ischemic conditioning, and electroacupuncture can promote the release of exosomes and achieve various therapeutic effects through exosomes. Created with Microsoft PowerPoint 2021. Upward arrows indicate an increase, and downward arrows indicate a decrease. HIF: Hypoxia inducible transcription factor.

Figure 5

Exosome-based therapies for ischemic stroke. Combining exosomes with drugs can improve their stability, efficiency, and bioavailability and reduce side effects. When combined with stents, exosomes can promote endothelial growth and reduce the risk of in-stent restenosis. Created with Microsoft PowerPoint 2021. Upward arrows indicate an increase, and downward arrows indicate a decrease. tPA: Tissue plasminogen activator.