Lipid Nanoparticles
Image Credit: Courtesy of Adelaide University
Scientific Frontline: Extended "At a Glance" Summary: Smart Nanoparticles Reprogram Tumor Microenvironments
The Core Concept: Researchers have engineered lipid nanoparticles that deliver mRNA technology to tumor-associated macrophages (TAMs), reprogramming these immune cells from tumor-supporting to cancer-fighting.
Key Distinction/Mechanism: Instead of attacking TAMs, which are large white blood cells that help tumors evade the immune system, the nanoparticles are coated with an antibody targeting the TREM2 protein on the macrophages. Once inside, they deliver mRNA to produce the CXCL9 chemical signal and Resiquimod, which collectively switch the macrophages' behavior and attract cancer-fighting T cells.
Major Frameworks/Components:
- Lipid Nanoparticles: Utilizes the same delivery mechanism as COVID-19 mRNA vaccines.
- Tumor-Associated Macrophages (TAMs): The specific immune cells targeted for reprogramming.
- TREM2 Protein: The target for the nanoparticle's antibody coating, allowing entry into the TAMs.
- mRNA & CXCL9: mRNA instructions prompt the production of CXCL9, a chemical beacon that attracts cancer-fighting CD8+ T cells.
- Resiquimod: A compound delivered alongside the mRNA that helps reverse the immune-suppressing behavior of the macrophages.
Branch of Science: Immunology, Oncology, Biomedical Engineering, Chemical Engineering.
Future Application: The technology provides a proof of concept for improving immunotherapies for solid cancers by modifying the tumor microenvironment to allow immune cells to remain active and effectively target the tumor. Future applications may also include combining this method with existing immune checkpoint-blocking drugs (targeting PD-L1 and CTLA-4) to foster long-term immune memory against cancer.
Why It Matters: A primary challenge in cancer immunotherapy is that the tumor microenvironment suppresses the body's immune cells. This targeted mRNA delivery method successfully alters that environment from the inside out, demonstrating a 60% reduction in suppressive macrophages and a fourfold increase in CXCL9 in animal models.
Adelaide University researchers have developed a new way of using mRNA technology to reprogram tumor-supporting immune cells and strengthen the body’s anticancer immune response.
The scientific team, spanning engineering, biomedical, oncology, and immunology experts, has developed tiny, targeted particles that could help the immune system fight cancer by reprogramming immune cells within the tumor environment.
The new approach uses lipid nanoparticles—the same delivery technology used to deliver mRNA in COVID-19 vaccines—to target a type of immune cell that can help tumors evade the body’s defenses.
In animal experiments, the nanoparticles were designed to find tumor-associated macrophages, or TAMs, which are large white blood immune cells commonly found in tumors.
Rather than attacking these cells, the researchers effectively reprogrammed them so they became less suppressive and helped attract cancer-fighting T cells into the tumor.
Lead researcher Professor Chunxia Zhao from Adelaide University’s School of Chemical Engineering said the research tackles a major challenge in cancer immunotherapy—getting immune cells into tumors and keeping them active.
“One of the biggest challenges in cancer immunotherapy is that the immune system may be capable of attacking a tumor, but the tumor environment can stop those immune cells from doing their job,” Professor Zhao said.
“Our approach is designed to change that environment from within the tumor. By specifically targeting tumor-associated macrophages, we can deliver the treatment where it is needed and encourage the immune system’s cancer-fighting T cells to enter the tumor and become more active.”
The nanoparticles were coated with an antibody that recognizes a protein called TREM2, which is highly expressed on the tumor-associated macrophages.
Once inside the macrophages, the particles delivered two key ingredients: an mRNA molecule carrying instructions to produce a chemical signal called CXCL9 and a compound called resiquimod that helps switch the macrophages away from their immune-suppressing behavior.
CXCL9 acts like a chemical beacon, helping attract cancer-fighting CD8+ T cells into the tumor.
In mouse experiments, treatment reduced the proportion of immune-suppressing macrophages by more than 60% and increased CXCL9 levels in tumors fourfold. The researchers also observed greater numbers and activity of cancer-fighting T cells and a moderate reduction in tumor growth.
When the treatment was combined with existing immune checkpoint-blocking drugs targeting PD-L1 and CTLA-4, the researchers saw further increases in cancer-fighting T cells and the development of central memory T cells, which could help the immune system remember and respond to cancer in the future. However, the combination did not produce additional tumor-growth inhibition in this particular mouse model.
Professor Zhao said the findings could open a new avenue for improving immunotherapy for solid cancers, where the tumor environment can prevent immune treatments from working effectively.
“This is an important proof of concept that we can use mRNA and nanoparticle technology to reprogram the immune environment of a tumor.
“There is still significant work to do before this approach could be considered for patients, but these results provide an encouraging foundation for developing more targeted cancer immunotherapies.”
Additional information: The research was led by Adelaide University researchers in collaboration with SA Pathology and the Royal Adelaide Hospital.
Published in journal: Science Advances
Authors: Rui Chen, Letao Xu, Alexander H. Staudacher, Xing Wang, Ruoxuan Jia, John W. Finnie, Xiaoyan Wang, Dawn M. Whelan, Michael P. Brown, and Chun-Xia Zhao
Source/Credit: Adelaide University
Edited by: Scientific Frontline
Reference Number: imgy091226_01