Multiple strategies to improve the therapeutic efficacy of mesenchymal stem cell‑derived exosome transplantation in ischemic stroke (Review)

Ischemic stroke (IS) is a common cause of physical disability and death worldwide. Although it has been indicated that mesenchymal stem cells (MSCs) can treat IS through mechanisms such as immunomodulation, angiogenesis and neuroprotection, their clinical application is limited by inherent drawbacks, such as immune rejection risk and tumorigenic potential. Notably, MSC‑derived exosomes (MSC‑Exos) possess advantages, such as a smaller volume, low immunogenicity and low tumorigenicity, enabling therapeutic effects similar to those of the parent cells. Furthermore, MSC‑Exos can carry various bioactive substances and cross the blood‑brain barrier (BBB), thus indicating their potential in the diagnosis, treatment and prognostic assessment of IS. The present review comprehensively elaborates on the principles by which MSC‑Exos may treat IS through mechanisms such as inhibiting inflammatory responses, suppressing apoptosis, promoting angiogenesis, regulating ferroptosis and maintaining BBB integrity. However, the therapeutic efficacy of MSC‑Exo monotherapy is restricted by its low brain bioavailability, short lesion retention time, insufficient in vivo stability and inability to remain at the lesion site for an extended period of time to exert its effect. Furthermore, the review summarizes the recent optimization strategies involving the combination of MSC‑Exos with microRNAs, traditional Chinese medicine, hydrogels, exosome pretreatment and electroacupuncture to enhance the efficacy of MSC‑Exo therapy for IS, and systematically reviews their synergistic therapeutic mechanisms. In addition, the current status of clinical translation, technical breakthrough obstacles and future development directions for MSC‑Exo combination therapies in neurological diseases is outlined, providing a theoretical reference for innovative treatments of IS.