Cephalopod-Inspired Bioelectronic Control of Cellular Signaling

项目总结/摘要 细胞跨越生物体水平距离和难以克服的障碍进行有效通信的能力 生物屏障是生物学中最重要的基本现象之一。大量的文学作品 揭示了这种细胞与细胞之间的通讯是通过被称为细胞外的膜封闭颗粒介导的。 囊泡，由细胞释放到周围环境中，含有脂质、配体、核酸和 proteins.这种细胞外囊泡代表了仅有的天然非病毒结构之一， “源”细胞可以重新编程“靶”细胞的遗传和命运，因此，它们不仅涉及 几乎每一个细胞过程的调节，而且在人体内几乎每一个组织的发育中， 身体此外，这些囊泡在各种疾病状态和病理状况中发挥重要作用， 包括癌症进展、神经变性、肌肉骨骼疾病、心血管退化 代谢综合征和伤口愈合。鉴于它们的普遍性和重要的生物学作用， 在临床诊断和治疗方面具有很大的前景，但迄今为止，这种应用受到阻碍 通过与以下相关的关键挑战：1）从根本上理解源细胞中的细胞外囊泡形成， 2)以高产率用生物分子货物装载细胞外囊泡，3）可控地调节细胞外 用外部刺激产生囊泡，4）将细胞外囊泡递送到组织相关的靶细胞， 长度尺度，5）维持细胞外囊泡内化货物的长期生物活性，和6） 在活体动物中实施细胞外囊泡治疗策略。在此，通过汲取灵感 从头足类动物皮肤细胞中发现的蛋白质和结构， 对于头足类启发的生物电子设备，我们建议解决所有的科学和技术问题， 目前阻碍细胞外囊泡临床应用的挑战。设想的研究计划 涉及1）验证用于控制细胞外囊泡从遗传上释放的电技术， 工程细胞与不同的生物电子设备和平台接口，2）开发策略， 远程和无线控制装载生物分子的细胞外囊泡从 工程细胞连接到可植入的生物电子系统中，以及3）证明远程控制 通过植入的生物电子系统集成释放临床上有价值的负载货物的细胞外囊泡 源细胞可以指导活动物中的靶细胞命运和组织发育。总之，成功的 这项工作的完成将使利用细胞外囊泡介导的细胞间 通信途径的调节生理过程，从而将提供变革性的 开发前所未有的下一代诊断和治疗技术的机会。

Project Summary/Abstract The ability of cells to efficiently communicate across organismal-level distances and difficult-to-surmount biological barriers is one of the most important fundamental phenomena in biology. A vast body of literature has revealed that such cell-to-cell communication is mediated via membrane-enclosed particles called extracellular vesicles, which are released by cells into their surroundings and contain lipids, ligands, nucleic acids, and proteins. Such extracellular vesicles represent one of the only natural non-viral structures by means of which “source” cells can reprogram the genetics and fate of “target” cells, and as such, they are implicated not only in the regulation of nearly every cellular process but also in the development of nearly every tissue within the human body. Moreover, these vesicles play essential roles in various disease states and pathological conditions, including cancer progression, neurodegeneration, musculoskeletal disorders, cardiovascular degradation, metabolic syndromes, and wound healing. Given their ubiquity and crucial biological roles, extracellular vesicles hold great promise for clinical diagnostics and therapeutics, but to date, such applications have been hindered by key challenges associated with 1) fundamentally understanding extracellular vesicle formation in source cells, 2) loading extracellular vesicles with biomolecular cargo in high yield, 3) controllably regulating extracellular vesicle production with external stimuli, 4) delivering extracellular vesicles to target cells over tissue-relevant length scales, 5) maintaining the long-term biological activity of extracellular vesicle-internalized cargo, and 6) implementing extracellular vesicle-based treatment strategies in living animals. Herein, by drawing inspiration from proteins and structures found in cephalopod skin cells and leveraging the technical foundation established for cephalopod-inspired bioelectronic devices, we propose to solve all of the scientific and technological challenges currently impeding clinical applications of extracellular vesicles. The envisioned research plan involves 1) validating electrical techniques for controlling the release of extracellular vesicles from genetically engineered cells interfaced with different bioelectronic devices and platforms, 2) developing strategies for remotely and wirelessly controlling the release of biomolecular cargo-loaded extracellular vesicles from engineered cells interfaced into implantable bioelectronic systems, and 3) demonstrating that remotely controlled release of clinically valuable cargo-loaded extracellular vesicles by implanted bioelectronic system-integrated source cells can guide target cell fate and tissue development in living animals. Altogether, the successful completion of the proposed work will enable harnessing of extracellular vesicle-mediated cell-to-cell communication pathway for the regulation of physiological processes and will thus furnish transformative opportunities for developing unprecedented next generation diagnostic and therapeutic technologies.