A Convergent Bioengineered Platform for Multifunctional Therapeutic Exosomes

多功能治疗性外泌体的融合生物工程平台

• 批准号: 10713513
• 负责人: Yichun Wang
• 金额: $ 37.09万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713513
• 关键词: Address; Antineoplastic Agents; Biomanufacturing; Biomedical Engineering; Bioreactors; Clinic; Clinical; Combined Modality Therapy; Dendrimers; Development; Diameter; Disease; Drug Delivery Systems; Endowment; Engineering; Eukaryotic Cell; Formulation; Gene Delivery; Goals; Hybrids; Ligands; Liposomes; Molecular; Natural regeneration; Near-infrared optical imaging; Neoplasm Metastasis; Nucleic Acids; Pharmaceutical Preparations; Phenotype; Play; Polymers; Production; Property; Proteins; Quantum Dots; RNA; Research; System; Technology; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; anticancer activity; biomaterial compatibility; blood-brain barrier crossing; blood-brain barrier penetration; cancer therapy; comparative efficacy; delivery vehicle; engineered exosomes; exosome; extracellular vesicles; graphene; image guided; immunogenicity; improved; in vivo; innovation; manufacture; nanocarrier; nanofiber; nanoparticle; nanoscale; nuclease; nucleic acid-based therapeutics; pharmacokinetics and pharmacodynamics; scaffold; targeted delivery; therapeutic protein; transcriptomics; uptake

A Convergent Bioengineered Platform for Multifunctional Therapeutic Exosomes Abstract: The overall goal of this MIRA application is to develop a convergent bioengineered platform for manufacturing and engineering therapeutic exosomes. The platform will allow the loading of drugs into exosomes with high efficiency, biomanufacturing of exosomes in high throughput, and further engineering exosome-based drug delivery systems for various diseases with desired functions including targeted delivery, tracking, and combinational therapies. Exosomes are a subset of extracellular vesicles, with diameters between 50 nm and 150 nm, secreted by most eukaryotic cells. They are very promising drug delivery vehicles due to their small size, biocompatibility, low immunogenicity, and reduced toxicity in comparison with synthetic nanoscale formulations such as liposomes, dendrimers, and polymers. Delivery of anticancer drugs contained in exosomes demonstrated improved pharmacokinetic and pharmacodynamic properties and enhanced anticancer activity in vivo compared to free drug molecules. Loading of therapeutic nucleic acids into exosomes protects the nucleic acids from nucleases and increases cellular uptake and the therapeutic effect due to specific molecular mechanisms of exosome internalization. Exosomes can cross the blood brain barrier and penetrate deep tissues with improved efficacy compared to that of synthetic nanocarriers. Moreover, they play a key role in cancer metastasis and regeneration by inducing transcriptomic and phenotypic changes with their RNA and protein cargoes. Therefore, they can potentially be reengineered for delivery of gene and protein therapeutics. However, there remain fundamental challenges to the utilization of exosomes in the clinic: i) drug loading efficiency into exosomes is very limited; ii) the production of exosomes has yet to reach sufficiently high throughput for clinical tests or even further development; and iii) endowing exosomes with multiple abilities for satisfactory disease targeting, tracking and combinational therapies is highly demanding. To address these challenges, the PI proposes the following three projects: 1) Developing a high-efficiency exosome drug loading technology with chiral graphene nanoparticles; 2) Developing an exosome production bioreactor with stimulating piezoelectric nanofibrous scaffolds; and 3) Engineering hybrid exosomes as a multifunctional targeted delivery system with targeting ligands and functional chiral graphene quantum dots for near-infrared imaging-guided photothermal cancer therapies. The proposed research contains several innovative approaches of exosome production, loading and engineering that, if successful and integrated, will provide a high-throughput and high-efficiency exosome manufacturing platform for drug delivery, and expand exosome-based drug delivery to diverse biomedical and clinic applications by combining the merits of both the native exosomes and synthetic nanoparticles.

多功能治疗外泌体的收敛生物工程平台 摘要：此MIRA应用的总体目标是开发一个收敛的生物工程平台 制造和工程治疗外泌体。该平台将允许将药物加载到外泌体中 效率高，外泌体的生物制造高吞吐量以及进一步的工程外泌体 具有所需功能的各种疾病的药物输送系统，包括目标交付，跟踪和 组合疗法。外泌体是细胞外囊泡的子集，直径在50 nm至150之间 NM，大多数真核细胞分泌。由于它们的尺寸很小，它们是非常有前途的吸毒车辆， 与合成纳米级配方相比，生物相容性，免疫原性低和毒性降低 例如脂质体，树枝状聚合物和聚合物。外泌体中包含的抗癌药物的递送 相比 释放药物分子。将治疗性核酸加载到外泌体中可保护核酸免受 由于特定的分子机制，核酸酶和增加了细胞摄取和治疗作用 外泌体内在化。外泌体可以越过血脑屏障，并通过改善 与合成纳米载体相比，功效。此外，它们在癌症转移和 通过其RNA和蛋白质货物诱导转录组和表型的变化来再生。所以， 它们可能会被重新设计用于递送基因和蛋白质疗法。但是，仍然存在 诊所中外泌体利用的基本挑战：i）将药物载荷效率为外泌体是 非常有限； ii）外泌体的产生尚未达到临床测试甚至 进一步发展； iii）赋予具有多种能力的外泌体，以实现令人满意的疾病靶向， 跟踪和组合疗法高度要求。为了应对这些挑战，PI提出了 以下三个项目：1）用手性石墨烯开发高效的外泌体药物加载技术 纳米颗粒； 2）使用刺激的压电纳米纤维开发外泌体生产生物反应器 脚手架； 3）工程混合外部外泌体作为一种具有靶向的多功能靶向输送系统 近红外成像引导的光热癌的配体和功能性手性石墨烯量子点 疗法。拟议的研究包含了外泌体生产，装载和的几种创新方法 如果成功和集成的工程将提供高通量和高效率外泌体 用于药物输送的制造平台，并将基于外部的药物扩展到多种生物医学和 通过结合天然外泌体和合成纳米颗粒的优点来进行诊所应用。