Insulin- inspired hippocampal neuron-targeting technology for protein drug delivery

• 成果类型: Article
• 署名作者: Kamei, Noriyasu; Ikeda, Kento; Ohmoto, Yuka; Fujisaki, Seita; Shirata, Ryusei; Maki, Maya; Miyata, Mika; Miyauchi, Yuki; Nishiyama, Nanaka; Yamada, Mana; Ohigashi, Yuna; Takeda-Morishita, Mariko
• 署名单位: Kobe Gakuin University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9286
• DOI: 10.1073/pnas.2407936121
• 发表日期: 2024-09-30
• 关键词: transferrin receptor antibody; brain delivery; sirna; transport; membrane; dynamin; neck

摘要

Hippocampal neurons can be the first to be impaired with neurodegenerative disorders, including Alzheimer's disease (AD). Most drug candidates for causal therapy of AD cannot either enter the brain or accumulate around hippocampal neurons. Here, we genetically engineered insulin- fusion proteins, called hippocampal neuron-targeting (Ht) proteins, for targeting protein drugs to hippocampal neurons because insulin tends to accumulate in the neuronal cell layers of the hippocampus. In vitro examinations clarified that insulin and Ht proteins were internalized into the cultured hippocampal neurons through insulin receptor-mediated macropinocytosis. Cysteines were key determinants of the delivery of Ht proteins to hippocampal neurons, and insulin B chain mutant was most potent in delivering cargo proteins. In vivo accumulation of Ht proteins to hippocampal neuronal layers occurred after intracerebroventricular administration. Thus, hippocampal neuron-targeting technology can provide great help for developing protein drugs against neurodegenerative disorders.