Intranasal Delivery of BACE1 siRNA and Berberine via Engineered Stem Cell Exosomes for the Treatment of Alzheimer’s Disease

作者：Chunbin Sun, Sha Sh, Yi Shan, Xiaoyu Gao, Liang Li, Cencan Xing, Zhongbao Guo, Hongwu Du · 发表于：International Journal of Nanomedicine · 年份：2025 · DOI：10.2147/ijn.s506793 · 被引用次数：49 · 研究领域：Extracellular vesicles in disease、Barrier Structure and Function Studies、Neurogenesis and neuroplasticity mechanisms

Introduction: Alzheimer's disease (AD) is a common progressive and irreversible neurodegenerative disease. AD accounts for 60%-70% of all dementia cases, ranking as the seventh leading cause of death globally. Human umbilical cord mesenchymal stem cells (hUC-MSCs) characterized by their abundant availability and low immunogenicity, have demonstrated significant therapeutic potential for AD in both preclinical studies and clinical trials. The use of exosomes can help mitigate the issues associated with cellular therapies. However, the clinical application of hUC-MSCs remains challenging due to their inability to effectively traverse the blood-brain barrier (BBB) and reach pathological sites. Therapeutic strategies utilizing exosomes derived from hUC-MSCs (Exos) have emerged as an effective approach for AD intervention. Methods: Here, we used ultrasound to construct multifunctional Exos (MsEVB@R/siRNA) for AD therapy. We obtained small interfering RNA for β-site precursor protein lyase-1 (BACE1 siRNA) and berberine for co-delivery into the brain. Berberine, a classical anti-inflammatory agent, effectively alleviates neuroinflammation in AD pathogenesis. BACE1 serves as the pivotal cleavage enzyme in amyloid β-protein (Aβ) formation, where silencing BACE1 synthesis through BACE1 siRNA significantly reduces Aβ production. In a 5xFAD mouse model, Exos selectively targeted microglial and neuronal cells after nasal delivery under the action of neural cell-targeting peptide rabies vi...