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

基本信息

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
项目类别：
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

项目摘要

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融合生物工程平台摘要：MIRA 应用的总体目标是开发一个融合生物工程平台制造和工程治疗性外泌体。该平台将允许将药物装载到外泌体中高效、高通量地生物制造外泌体，并进一步工程化外泌体针对各种疾病的药物输送系统具有所需的功能，包括靶向输送、跟踪和联合疗法。外泌体是细胞外囊泡的一个子集，直径在 50 nm 至 150 nm 之间 nm，由大多数真核细胞分泌。由于尺寸小，它们是非常有前途的药物输送工具，与合成纳米级制剂相比，具有生物相容性、低免疫原性和更低的毒性例如脂质体、树枝状聚合物和聚合物。外泌体中包含的抗癌药物的递送被证明与相比，改善了药代动力学和药效学特性并增强了体内抗癌活性释放药物分子。将治疗性核酸装载到外泌体中可以保护核酸免受核酸酶并通过特定的分子机制增加细胞摄取和治疗效果外泌体内化。外泌体可以穿过血脑屏障并穿透深层组织，并具有改善的作用与合成纳米载体相比的功效。此外，它们在癌症转移和通过利用其 RNA 和蛋白质货物诱导转录组和表型变化来实现再生。所以，它们有可能被重新设计用于传递基因和蛋白质疗法。然而，仍然存在外泌体在临床上的应用面临的根本挑战：i) 外泌体的载药效率是非常有限； ii) 外泌体的生产尚未达到足够高的通量以进行临床测试，甚至进一步发展； iii) 赋予外泌体多种令人满意的疾病靶向能力，追踪和联合治疗的要求很高。为了应对这些挑战，PI 提出以下三个项目：1）开发手性石墨烯高效外泌体载药技术纳米颗粒； 2）开发具有刺激压电纳米纤维的外泌体生产生物反应器脚手架； 3) 将混合外泌体设计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性手性石墨烯量子点疗法。拟议的研究包含外泌体生产、装载和运输的几种创新方法如果工程成功并整合，将提供高通量和高效的外泌体药物递送制造平台，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的优点来临床应用。