(1) Dong S (2) Liu X (3) Bi Y (4) Wang Y (5) Antony A (6) Lee D (7) Huntoon K (8) Jeong S (9) Ma Y (10) Li X (11) Deng W (12) Schrank BR (13) Grippin AJ (14) Ha J (15) Kang M (16) Chang M (17) Zhao Y (18) Sun R (19) Sun X (20) Yang J (21) Chen J (22) Tang SK (23) Lee LJ (24) Lee AS (25) Teng L (26) Wang S (27) Teng L (28) Kim BYS (29) Yang Z (30) Jiang W

Nature communications

The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-_ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic sEVs (imsEV) preferentially target glioblastoma cells and generate potent antitumour activities in vivo, including against tumours intrinsically resistant to immunotherapy. Together, these results provide an adaptive approach to engineering mRNA-loaded sEVs with targeting functionality and pave the way for their adoption in cancer immunotherapy applications.

Author Info: (1) School of Life Science, Jilin University, Changchun, 130012, China. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

Author Info: (1) School of Life Science, Jilin University, Changchun, 130012, China. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (2) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. Chemical Engineering, Institute for Micromanufacturing, Louisiana Tech University, Ruston, LA, 71272, USA. (3) Practice Training Center, Changchun University of Chinese Medicine, Changchun, 130117, China. (4) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (5) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (6) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (7) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (8) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (9) Department of Biomedical Engineering, The Ohio State University, Columbus, OH, 43210, USA. (10) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (11) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (12) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (13) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (14) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (15) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (16) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (17) School of Life Science, Jilin University, Changchun, 130012, China. (18) School of Life Science, Jilin University, Changchun, 130012, China. (19) School of Life Science, Jilin University, Changchun, 130012, China. (20) School of Life Science, Jilin University, Changchun, 130012, China. (21) School of Life Science, Jilin University, Changchun, 130012, China. (22) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (23) Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA. Spot Biosystems Ltd., Palo Alto, CA, 94305, USA. (24) Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518055, China. School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. (25) School of Life Science, Jilin University, Changchun, 130012, China. (26) Chemical Engineering, Institute for Micromanufacturing, Louisiana Tech University, Ruston, LA, 71272, USA. swang@latech.edu. (27) School of Life Science, Jilin University, Changchun, 130012, China. tenglesheng@jlu.edu.cn. (28) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. bykim@mdanderson.org. Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. bykim@mdanderson.org. (29) School of Life Science, Jilin University, Changchun, 130012, China. zhaogangyang@jlu.edu.cn. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. zhaogangyang@jlu.edu.cn. (30) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. wjiang4@mdanderson.org. Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. wjiang4@mdanderson.org.

Citation: Nat Commun 2023 Oct 19 14:6610 Epub10/19/2023

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/37857647

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