Endoscopic nasal delivery of engineered endothelial progenitor cell-derived exosomes improves angiogenesis and neurological deficits in rats with intracerebral hemorrhage

Gui Wan; Zhenwei Li; Lingui Gu; Ye Sun; Yuhe Wang; Yiqing Wang; Ruxu Geng; Yangyang Chen; Wenbin Ma; Xinjie Bao; Renzhi Wang

doi:10.1016/j.mtbio.2025.101652

Endoscopic nasal delivery of engineered endothelial progenitor cell-derived exosomes improves angiogenesis and neurological deficits in rats with intracerebral hemorrhage

Mater Today Bio. 2025 Mar 11:32:101652. doi: 10.1016/j.mtbio.2025.101652. eCollection 2025 Jun.

Authors

Gui Wan¹, Zhenwei Li¹, Lingui Gu¹, Ye Sun¹, Yuhe Wang¹, Yiqing Wang¹, Ruxu Geng¹, Yangyang Chen², Wenbin Ma¹, Xinjie Bao^{1

3}, Renzhi Wang^{1

4}

Affiliations

¹ Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
² Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical College, Hefei, 230031, China.
³ State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing, China.
⁴ School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.

Abstract

Intracerebral hemorrhage (ICH) remains a life-threatening condition due to its high mortality and limited treatment options. This study explores a novel therapeutic strategy using engineered exosomes derived from endothelial progenitor cells (EPC-EXOs) to improve ICH outcomes. EPC-EXOs were modified with a CD47-enriched red blood cell membrane via co-extrusion to enhance their anti-phagocytic properties, thereby reducing degradation by activated microglia after ICH. A minimally invasive endoscopic-guided delivery system was developed to facilitate the targeted intranasal administration of these engineered EPC-EXOs (m-Oe-EXOs), allowing direct entry into brain tissue. We confirmed m-Oe-EXOs' high retention and effective distribution in the brain. Functional analysis demonstrated that EPC-EXOs significantly promoted the proliferation, migration, and angiogenesis of brain microvascular endothelial cells (BMECs), with proteomic analysis identifying HSP90 as a key protein activating the Akt pathway in BMECs. In vivo, m-Oe-EXOs demonstrated therapeutic efficacy by improving blood-brain barrier integrity, reducing hematoma volume, and enhancing neurological recovery in ICH rats. Collectively, our findings highlight the potential of minimally invasive, endoscopic-guided delivery of m-Oe-EXOs as an innovative approach for ICH treatment, providing new insights into targeted, exosomes-based regenerative therapies.

Keywords: Blood-brain barrier; Brain microvascular endothelial cells; Endothelial progenitor cell exosomes; HSP90; Intracerebral hemorrhage; Nasal endoscopic delivery.