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; 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.

项目摘要 拟议的研究项目解决了对Smart和Smart的生物工程方法的需求 靶向外泌体的治疗递送平台，可以在心肌梗塞后促进组织修复 （Mi）。在临床前和临床环境中累积的证据始终表明外泌体 由成人茎/基质细胞分泌 MI后受伤的心肌受伤。基于外泌体的治疗剂代表了从常规的范式转变 基于细胞的心血管疗法的方法。但是，目前基于外泌体的治疗剂遭受 几个问题，包括缺乏目标性，复杂的制造过程来加载其他治疗性 兑换费和费用。此外，能够控制外泌体产品的技术具有 尚待探索。为了克服这些挑战，我们建议开发出智能的心脏治疗性 纳米胶囊（Cardioxo），用于两个间充质干细胞衍生的靶向和受控递送 外泌体（MSC-EXO）和治疗蛋白，可在MI后促进心脏修复。我们的中心假设是 （1）用外泌体和心脏保护蛋白官能化的有氧运动（例如，原肌蛋白2，Agrin，Agrin， 胰岛素样生长因子1，髓样衍生的生长因子）可以通过一层静电层设计 组装过程与新型酶介导的自由基聚合（EMRP）技术相结合； （2） CarcioXO可以响应基质的上调，使组合治疗剂的递送 金属蛋白酶（MMP）是心脏缺血性损伤的标志，并触发了修复信号通路 由治疗蛋白介导的修复缺血性心脏。拟议的有氧策略的创新 包括（1）靶向受伤的心肌细胞； （2）能够在on- 通过利用缺血性心脏的心脏病理来需求时尚； （3）双重再生机制 靶向心脏修复，结合了外泌体介导的旁分泌机制，类似于干细胞疗法 带有心脏保护蛋白介导的信号通路。我们将制造和优化Cardioxo 装有各种心脏保护蛋白，并评估心脏XO的体外生物活性。安全， 功能益处，将研究有氧疗法的潜在作用模式 缺血性心损伤。拟议的研究项目的成功执行将建立一个温和的 外泌体功能化的方法，构成了创新和现成的外泌体的基础 基于基于智能和靶向纳米医学的疗法，用于修复和再生MI心脏。 尽管此特定的赠款应用程序针对心脏，但CardioXO策略代表一个平台 可以推广到多个组织的修复和再生的技术。