Qiankun Zhang,1 Yupeng Wang,2 Zhihan Zhu,1 Waqas Ahmed,1,3 Dongfang Zhou,2 Lukui Chen1 

1Department of Neurosurgery, Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 2Key Laboratory of Mental Health of the Ministry of Education, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People’s Republic of China; 3School of Medicine, Southeast University, Nanjing, People’s Republic of China

Correspondence: Lukui Chen, Department of Neurosurgery, Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, 510310, People’s Republic of China, Email neuro_clk@hotmail.com Dongfang Zhou, Key Laboratory of Mental Health of the Ministry of Education, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People’s Republic of China, Email dfzhou@smu.edu.cn

Background: Stroke has significantly contributed to the global mortality rate over the years, emphasizing the urgency of finding effective treatment strategies. Neural stem cell (NSC)-derived exosomes have the potential to improve neurological recovery after stroke; however, their therapeutic efficacy is hindered by their rapid clearance and limited duration of action. This study presents an innovative drug delivery method: a hydrogel based on NSC exosomes and hydroxypropyl methylcellulose (HPMC), which is intended to offer a continuous release, thereby enhancing and prolonging neurological improvement.
Results: We developed a nanohydrogel (Exo-HPMC) by integrating Buyang Huanwu Decoction (BHD) -preconditioned NSC-derived exosomes with HPMC. This study thoroughly investigated the controlled-release capabilities and rheological properties of Exo-HPMC. Our findings show that Exo-HPMC enables effective sustained exosome release, significantly extending their retention in mice. When administered to mice with middle cerebral artery occlusion (MCAO), Exo-HPMC facilitated notable post-stroke neurorepair. Behavioral assessments and immunofluorescence staining demonstrated that exosomes significantly promoted angiogenesis and nerve regeneration in stroke-affected areas, thereby reversing programmed cell death.
Conclusion: The Exo-HPMC nanohydrogel presents a groundbreaking approach for stroke therapy. Ensuring a controlled and prolonged release of NSC-derived exosomes over two weeks, significantly enhances the therapeutic potential of exosomes for ischemic stroke treatment.

Keywords: stem cell, exosome, hydrogel, angiogenesis, neuroregeneration