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.

多功能治疗性外泌体的聚合生物工程平台 翻译后摘要：这个MIRA应用程序的总体目标是开发一个收敛的生物工程平台， 制造和工程化治疗性外泌体。该平台将允许将药物装载到外泌体中 以高效率、高通量生物制造外泌体，并进一步工程化基于外泌体的 用于各种疾病的药物递送系统，具有所需的功能，包括靶向递送、追踪和 联合疗法外泌体是细胞外囊泡的子集，直径在50 nm和150 nm之间 nm，由大多数真核细胞分泌。由于它们的小尺寸，它们是非常有前途的药物递送载体， 与合成纳米级制剂相比，生物相容性、低免疫原性和降低的毒性 例如脂质体、树枝状聚合物和聚合物。展示了外泌体中所含抗癌药物的递送 改善的药代动力学和药效学特性以及增强的体内抗癌活性 释放药物分子。将治疗性核酸装载到外来体中保护核酸免于 核酸酶和增加细胞摄取和治疗效果，由于特定的分子机制， 外泌体内化外泌体可以穿过血脑屏障并穿透深层组织， 与合成纳米载体相比的功效。此外，它们在癌症转移中起关键作用， 再生诱导转录组和表型的变化与他们的RNA和蛋白质货物。因此，我们认为， 它们可以潜在地被重新工程化以用于递送基因和蛋白质治疗剂。然而， 在临床中利用外来体的基本挑战是：i）将药物装载到外来体中的效率是 非常有限; ii）外泌体的产生尚未达到用于临床测试的足够高的通量，甚至 进一步发展;和iii）赋予外泌体以令人满意的疾病靶向的多种能力， 跟踪和组合疗法是非常苛刻的。为了应对这些挑战，PI建议 具体包括三个项目：1）开发手性石墨烯高效外泌体载药技术 2）开发具有刺激压电纳米纤维的外泌体生产生物反应器 3）工程化杂合外来体作为具有靶向性的多功能靶向递送系统 用于近红外成像引导光热癌症的配体和功能手性石墨烯量子点 治疗拟议的研究包含几种创新的外泌体生产，装载和运输方法。 工程，如果成功和整合，将提供高通量和高效率的外泌体 用于药物递送的制造平台，并将基于外泌体的药物递送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两者的优点，