A Convergent Bioengineered Platform for Multifunctional Therapeutic Exosomes

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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.