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Modulation of microglial polarization by sequential targeting surface-engineered exosomes improves therapy for ischemic stroke

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Abstract

Microglia are important cells that act on regulating neuroinflammation and neurofunction after the induction of ischemic stroke (IS). Consequently, the efficient accumulation of drugs within ischemic regions, particularly in microglia, serves as a valuable approach for achieving effective therapy by attenuating microglia-mediated cerebral ischemic injury. In this study, we designed mannose (man)-conjugated luteolin (lut)-loaded platelet-derived exosomes (lut/man-pEXO) as surface engineered multifunctional cascade-delivery drug carriers to target ischemic blood vessels and subsequent microglia to enhance drug accumulation and induce neuroprotection of neurovascular unit (NVU) against IS. The results revealed that as platelets naturally gathered in pathological ischemic cerebral vessels, lut/man-pEXO could bind to platelets and efficiently target ischemic injury sites. Moreover, owing to the selective binding affinity of mannose present in lut/man-pEXO towards the mannose receptor expressed on microglia, lut/man-pEXO exhibited superior microglia-targeting properties, inducing the increased uptake of lut by microglia. As a result, lut/man-pEXO regulated microglia by inhibiting the activation of detrimental M1 and promoting the transition towards the anti-inflammatory type (M2), thus attenuating ischemic damage of NVU by reducing the infarct area, rescuing the damage of blood–brain barrier (BBB) and preventing inflammatory transformation of astrocytes.

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All data generated or analyzed during this study are included in this published article.

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Acknowledgements

We thank Tao Xu, Hongdan Li, Jia Liang, and Song Zhao from the Life Science Institute of Jinzhou Medical University for their technical support.

Funding

This work was supported by grants of Project of Liaoning Educational Committee (JYTJCZR2020067 and JYTQN2020015). We thank the support of the above funds.

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Authors and Affiliations

  1. School of Pharmacy, Jinzhou Medical University, Jinzhou, 121000, People’s Republic of China

    Xintong Liu, Yunni Hao, Zhixuan Huang, Yijie Shi & Liang Zhao

  2. School of Veterinary Medicine, Jinzhou Medical University, Jinzhou, 121000, People’s Republic of China

    Chang Su

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  1. Xintong Liu
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  2. Yunni Hao
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  3. Zhixuan Huang
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Contributions

Conceptualization, C. S. and L. Z.; methodology, X. L.; validation, X. L., Y. H., and Z.H.; formal analysis, X. L. and Y. H.; investigation, X. L. and Y. S.; writing—original draft preparation, X. L.; writing—review and editing, L. Z.; supervision, C. S. and L. Z.; and funding acquisition, Y. S. and L. Z.

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Correspondence to Liang Zhao.

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Research experiments conducted in this article with animals were approved by the Ethical Committee and responsible authorities of Jinzhou Medical University following all guidelines, regulations, legal, and ethical standards as required for animals and followed the National Guidelines for Animal Protection.

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Liu, X., Hao, Y., Huang, Z. et al. Modulation of microglial polarization by sequential targeting surface-engineered exosomes improves therapy for ischemic stroke. Drug Deliv. and Transl. Res. 14, 418–432 (2024). https://doi.org/10.1007/s13346-023-01408-6

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