Exosome-Based Pathological Microenvironment-Responsive Nanocapsules for Targeted Heart Repair

基于外泌体的病理微环境响应纳米胶囊用于靶向心脏修复

• 批准号: 10382401
• 负责人: Teng Su
• 金额: $ 19.6万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382401
• 关键词: Address; Adult; Agrin; American; Applications Grants; Award; Biological Assay; Biomedical Engineering; Cardiac; Cardiac Myocytes; Cardiovascular system; Cause of Death; Cell Proliferation; Cell Therapy; Cells; Clinical; Electrostatics; Engineering; Enzymes; Fibrosis; Foundations; Growth Factor; Heart; Heart Injuries; Human; In Vitro; Inflammation; Injections; Injury; Insulin-Like Growth Factor I; Matrix Metalloproteinases; Mediating; Medicine; Mesenchymal Stem Cells; Modeling; Myelogenous; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Pathologic; Pathology; Process; Proteins; Rattus; Research Project Grants; Safety; Scheme; Series; Signal Pathway; Signal Transduction; Site; Stromal Cells; Technology; Testing; Therapeutic; Tissues; United States; Up-Regulation; Vesicle; base; cardiac regeneration; cardiac repair; cardioprotection; cost effective; design; exosome; injured; injury and repair; innovation; ischemic injury; nanocapsule; nanoformulation; nanomedicine; nanosized; novel; novel strategies; paracrine; particle; polymerization; pre-clinical; regenerative; repaired; response; stem; stem cell exosomes; stem cell therapy; stem cells; targeted treatment; therapeutic protein; tissue repair

PROJECT SUMMARY The proposed research project addresses the need for a bioengineering approach to a smart and targeted exosome-based therapeutic delivery platform that can promote tissue repair after myocardial infarction (MI). Accumulating evidence in both preclinical and clinical settings has consistently indicated the exosomes secreted from adult stem/stromal cells orchestrate the principal modes of action of cell therapy to repair the injured heart muscle following MI. Exosome-based therapeutics represent a paradigm shift from conventional cell-based approaches to cardiovascular therapy. However, current exosome-based therapeutics suffer from several problems including lack of targetability, complicated fabrication process to load additional therapeutic cargos, and expense. In addition, technologies that enable controlled delivery of exosome-based products have yet to be explored. To overcome these challenges, we propose to develop a smart cardiotherapeutic nanocapsule (CardioXo) for the targeted and controlled delivery of both mesenchymal stem cell-derived exosomes (MSC-Exo) and therapeutic proteins to promote heart repair post-MI. Our central hypotheses are that (1) the CardioXo functionalized with both exosomes and cardioprotective proteins (e.g., prokineticin 2, agrin, insulin-like growth factor 1, myeloid-derived growth factor) can be engineered via an electrostatic layer-by-layer assembly process combined with a novel enzyme-mediated radical polymerization (EMRP) technology; and (2) the CardioXo can enable the delivery of combination therapeutics in response to the upregulation of matrix metalloproteinases (MMPs), a hallmark of cardiac ischemic injury, and trigger the reparative signaling pathways mediated by therapeutic proteins to repair the ischemic heart. The innovation of the proposed CardioXo strategy includes (1) targeting to the injured cardiomyocytes; (2) ability to deliver combination therapeutics in an on- demand fashion by leveraging cardiac pathology in the ischemic heart; (3) dual-regenerative mechanism for targeted heart repair that combines the exosome-mediated paracrine mechanism similar to stem cell therapy with the cardioprotective protein-mediated signaling pathways. We will fabricate and optimize the CardioXo loaded with various cardioprotective proteins and assess the in vitro bioactivity of CardioXo. The safety, functional benefits, and the potential modes of action of CardioXo therapy will be investigated in rats with ischemic heart injury. Successful execution of the proposed research project will establish a mild and facile approach to exosome functionalization and form the foundation of an innovative and off-the-shelf exosome- based therapy based on smart and targeted nanomedicine for the repair and regeneration of the post-MI heart. Although this particular grant application targets the heart, the CardioXo strategy represents a platform technology that can be generalized to the repair and regeneration of multiple tissues.

项目概要 拟议的研究项目解决了对生物工程方法的需求，以实现智能和 基于外泌体的靶向治疗递送平台可促进心肌梗死后的组织修复 （MI）。临床前和临床环境中不断积累的证据一致表明外泌体 由成体干细胞/基质细胞分泌的细胞协调细胞疗法的主要作用模式以修复 心肌梗死后心肌损伤。基于外泌体的疗法代表了传统疗法的范式转变 基于细胞的心血管治疗方法。然而，目前基于外泌体的疗法存在以下问题： 存在一些问题，包括缺乏靶向性、加载额外治疗剂的复杂制造工艺 货物、费用。此外，能够控制递送基于外泌体的产品的技术已经 尚待探索。为了克服这些挑战，我们建议开发一种智能心脏治疗方法 纳米胶囊（CardioXo）用于定向和受控地输送间充质干细胞来源的 外泌体 (MSC-Exo) 和治疗蛋白可促进 MI 后心脏修复。我们的中心假设是 (1) CardioXo 与外泌体和心脏保护蛋白（例如前动力蛋白 2、agrin、 胰岛素样生长因子 1（骨髓源性生长因子）可以通过静电逐层进行工程改造 组装过程与新型酶介导自由基聚合（EMRP）技术相结合；和（2） CardioXo 可以根据基质的上调提供联合治疗 金属蛋白酶 (MMP) 是心脏缺血性损伤的标志，可触发修复信号通路 由治疗性蛋白质介导修复缺血的心脏。 CardioXo 战略的创新之处 包括（1）针对受损的心肌细胞； (2) 能够同时提供联合治疗 利用缺血性心脏的心脏病理学来需求时尚； (3)双重再生机制 靶向心脏修复结合了类似于干细胞治疗的外泌体介导的旁分泌机制 与心脏保护蛋白介导的信号通路。我们将制造和优化 CardioXo 加载各种心脏保护蛋白并评估 CardioXo 的体外生物活性。安全性， 将在患有以下疾病的大鼠中研究 CardioXo 疗法的功能益处和潜在作用模式 缺血性心脏损伤。拟议研究项目的成功执行将建立一个温和且容易的 外泌体功能化的方法，并形成创新和现成的外泌体的基础 基于智能和靶向纳米医学的治疗，用于心肌梗死后心脏的修复和再生。 尽管这个特殊的拨款申请针对的是心脏，但 CardioXo 策略代表了一个平台 可推广到多种组织修复和再生的技术。