Kanazawa University develops modified exosomes that selectively activate T-helper cells — Tumor reduction confirmed in mice

A research group led by Professor Rikinari Hanayama and Associate Professor Tomoyoshi Yamano of the WPI Nano Life Science Institute (NanoLSI) and Professor Mitsutoshi Nakada and Assistant Professor Ryouken Kimura of the Department of Neurosurgery in the Graduate School of Medical Sciences at Kanazawa University announced that they successfully artificially modified exosomes, which are microparticles secreted by cells, and developed "modified exosomes (AP-EV)" to selectively activate and induce differentiation of cancer antigen-specific T-helper cells. Using model mice experiments, they confirmed the induction of immune responses against cancer cells and tumor reduction. This technology is expected to be applied not only to cancer immunity but also to conditions involving excessive activation of the immune system, such as autoimmune diseases and allergies. The results were published in Drug Delivery on June 13.

Exosomes are membrane vesicles with a diameter of 50-100 nanometers that cells release to exchange information with other cells. They contain biomolecules such as proteins, lipids, RNA, and DNA. It is known that they also play a role in information transmission between immune cells, and that proteins and RNA molecules contained within them act on other immune cells, contributing to their activation or suppression. In recent years, exosomes have been shown to be involved in diseases, including cancer, and their application to diagnosis and treatment is expected. Modified exosomes are attracting particular attention because they can freely carry target proteins and nucleic acids.

The research group previously reported in March of this year the development of modified exosomes "AP-EV (antigen-presenting vesicles)" that selectively activate killer T cells (CTL) that directly attack cancer cells, demonstrating that immune cells can be precisely controlled by target.

In this study, they applied the same technology to design and create modified exosomes that selectively activate and induce differentiation of T-helper cells (Th1, Th2) that control immune responses. T-helper cells have the function of recognizing antigens from foreign substances and infections, regulating the activities of other immune cells, and enhancing the body's immune response. For T-helper cell differentiation, three elements are important: antigen recognition by T cell receptors (TCR), co-stimulation by co-stimulatory molecules, and differentiation promotion by cytokines (IL-12 or IL-4).

The group designed these modified exosomes to simultaneously present all of these elements on the exosome surface. They were named "AP-EV-Th1" and "AP-EV-Th2" respectively, according to the differences in cytokines that induce differentiation into Th1 type (cellular immunity) or Th2 type (humoral immunity).

In experiments using cultured cells, it was confirmed that AP-EV-Th1 and AP-EV-Th2 could selectively activate antigen-specific T-helper cells and induce differentiation into Th1 and Th2 types, respectively. Furthermore, in mouse experiments, administration of AP-EV-Th1 promoted T-helper cell activation and differentiation into Th1 type, significantly suppressing tumor growth.

Hanayama commented: "This modified exosome technology makes it possible to selectively control only the target immune cells within the body. This is expected to lead to the development of revolutionary treatments for various diseases, not limited to cancer. In the future, we aim to realize exosome-based drug development originating from Japan by establishing high-quality exosome pharmaceutical manufacturing and quality control technologies through collaboration with companies and regulatory authorities."

Journal Information
Publication: Drug Delivery
Title: Selective expansion and differentiation of antigen-specific CD4⁺ T-helper cells by engineered extracellular vesicles
DOI: 10.1080/10717544.2025.2509969