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

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. <i>In vivo</i>, 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.