Engineered Immunomodulatory Extracellular Vesicles from Epithelial Cells with the Capacity for Stimulation of Innate and Adaptive Immunity in Cancer and Autoimmunity

Authors

Xin Luo
Fernanda G Kugeratski
Dara P Dowlatshahi
Hikaru Sugimoto
Kent A Arian
Yibo Fan
Li Huang
Danielle Wills
Sergio Lilla
Kelly Hodge
Sara R Zanivan
Valerie S LeBleu
Kathleen M McAndrews
Raghu Kalluri

Language

English

Publication Date

2-11-2025

Journal

ACS Nano

DOI

10.1021/acsnano.4c09688

PMID

39869047

PMCID

PMC12043189

PubMedCentral® Posted Date

2-11-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Extracellular vesicles (EVs) are generated by all cells. Systemic administration of allogenic EVs derived from epithelial and mesenchymal cells have been shown to be safe, despite carrying an array of functional molecules, including thousands of proteins. To address whether epithelial cells derived EVs can be modified to acquire the capacity to induce immune response, we engineered 293T EVs to harbor the immunomodulatory molecules CD80, OX40L and PD-L1. We demonstrated abundant levels of these proteins on the engineered cells and EVs. Functionally, the engineered EVs efficiently elicited positive and negative co-stimulation of human and murine T cells. In the setting of cancer and autoimmune hepatitis, the engineered EVs modulated T cell functions and altered disease progression. OX40L EVs also provided enhanced anti-tumor activity in combination with anti-CTLA-4 in melanoma-bearing mice. In addition, we added multiple immunomodulatory proteins in EVs (EVmIM), attempting to elicit an immune response in both lymphoid and myeloid compartments. The EVmIM containing CD80, 4-1BBL, CD40L, CD2, and CD32 engaged both T cells and antigen presenting cells (APCs) in melanoma tumors, demonstrating the capacity for EVmIM to elicit anti-tumor activity. Our work provides evidence that EVs can be engineered to induce specific immune responses with translational potential to modulate immune cell functions in pathological settings.

Keywords

Animals, Extracellular Vesicles, Humans, Mice, Immunity, Innate, Epithelial Cells, Adaptive Immunity, Autoimmunity, B7-H1 Antigen, Mice, Inbred C57BL, B7-1 Antigen, HEK293 Cells, T-Lymphocytes, OX40 Ligand, Neoplasms, Immunomodulation, Extracellular vesicles, immunology, co-stimulation, cancer, autoimmunity

Published Open-Access

yes

Recommended Citation

Luo, Xin; Kugeratski, Fernanda G; Dowlatshahi, Dara P; et al., "Engineered Immunomodulatory Extracellular Vesicles from Epithelial Cells with the Capacity for Stimulation of Innate and Adaptive Immunity in Cancer and Autoimmunity" (2025). Faculty, Staff and Student Publications. 5939.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5939