ICAM-1-decorated extracellular vesicles loaded with miR-146a and Glut1 drive immunomodulation and hinder tumor progression in a murine model of breast cancer

Silvia Duarte-Sanmiguel; Ana I. Salazar-Puerta; Ana Panic; Daniel Dodd; Carlie Francis; Diego Alzate-Correa; Lilibeth Ortega-Pineda; Luke Lemmerman; Maria A. Rincon-Benavides; Kavya Dathathreya; William Lawrence; Neil Ott; Jingjing Zhang; Binbin Deng; Shipeng Wang; Sandra P. Santander; David W. McComb; Eduardo Reategui; Andre F. Palmer; William E. Carson; Natalia Higuita-Castro; Daniel Gallego-Perez

doi:10.1039/D3BM00573A

ICAM-1-decorated extracellular vesicles loaded with miR-146a and Glut1 drive immunomodulation and hinder tumor progression in a murine model of breast cancer†

Silvia Duarte-Sanmiguel,^a Ana I. Salazar-Puerta,^ab Ana Panic,^a Daniel Dodd,

^ac Carlie Francis,^a Diego Alzate-Correa,^ab Lilibeth Ortega-Pineda,^a Luke Lemmerman,^a Maria A. Rincon-Benavides,^abd Kavya Dathathreya,^a William Lawrence,

^ac Neil Ott,^a Jingjing Zhang,^e Binbin Deng,^f Shipeng Wang,^a Sandra P. Santander,

^g David W. McComb,^fh Eduardo Reategui,^e Andre F. Palmer,^e William E. Carson,ⁱ Natalia Higuita-Castro*^abdijk and Daniel Gallego-Perez

*^abdij

Author affiliations

* Corresponding authors

^a The Ohio State University, Department of Biomedical Engineering, Columbus, OH 43210, USA
E-mail: gallegoperez.1@osu.edu, higuitacastro.1@osu.edu

^b The Ohio State University, Gene Therapy Institute, Columbus, OH 43210, USA

^c The Ohio State University, Biomedical Sciences Graduate Program, Columbus, OH 43210, USA

^d The Ohio State University, Biophysics Program, Columbus, OH 43210, USA

^e The Ohio State University, William G. Lowrie Department of Chemical and Biomolecular Engineering, Columbus, OH 43210, USA

^f The Ohio State University, Center for Electron Microscopy and Microanalysis (CEMAS), Columbus, OH 43210, USA

^g Juan N. Corpas University Foundation, Center of Phytoimmunomodulation Department of Medicine, Bogota, Colombia

^h The Ohio State University, Department of Materials Science and Engineering, Columbus, OH 43210, USA

ⁱ The Ohio State University, Department of Surgery, Columbus, OH 43210, USA

^j The Ohio State University, Dorothy M. Davis Heart and Lung Research Institute, Columbus, OH 43210, USA

^k The Ohio State University, Department of Neurological Surgery, Columbus, OH, 43210, USA

Abstract

Tumor-associated immune cells play a crucial role in cancer progression. Myeloid-derived suppressor cells (MDSCs), for example, are immature innate immune cells that infiltrate the tumor to exert immunosuppressive activity and protect cancer cells from the host's immune system and/or cancer-specific immunotherapies. While tumor-associated immune cells have emerged as a promising therapeutic target, efforts to counter immunosuppression within the tumor niche have been hampered by the lack of approaches that selectively target the immune cell compartment of the tumor, to effectively eliminate “tumor-protecting” immune cells and/or drive an “anti-tumor” phenotype. Here we report on a novel nanotechnology-based approach to target tumor-associated immune cells and promote “anti-tumor” responses in a murine model of breast cancer. Engineered extracellular vesicles (EVs) decorated with ICAM-1 ligands and loaded with miR-146a and Glut1, were biosynthesized (in vitro or in vivo) and administered to tumor-bearing mice once a week for up to 5 weeks. The impact of this treatment modality on the immune cell compartment and tumor progression was evaluated via RT-qPCR, flow cytometry, and histology. Our results indicate that weekly administration of the engineered EVs (i.e., ICAM-1-decorated and loaded with miR-146a and Glut1) hampered tumor progression compared to ICAM-1-decorated EVs with no cargo. Flow cytometry analyses of the tumors indicated a shift in the phenotype of the immune cell population toward a more pro-inflammatory state, which appeared to have facilitated the infiltration of tumor-targeting T cells, and was associated with a reduction in tumor size and decreased metastatic burden. Altogether, our results indicate that ICAM-1-decorated EVs could be a powerful platform nanotechnology for the deployment of immune cell-targeting therapies to solid tumors.

This article is part of the themed collection: Biomaterials Science Emerging Investigator Series

Biomaterials Science

ICAM-1-decorated extracellular vesicles loaded with miR-146a and Glut1 drive immunomodulation and hinder tumor progression in a murine model of breast cancer†

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ICAM-1-decorated extracellular vesicles loaded with miR-146a and Glut1 drive immunomodulation and hinder tumor progression in a murine model of breast cancer

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