Natural killer cells can be engineered directly inside the human body using lipid nanoparticles carrying messenger RNA, offering a streamlined approach to treating cancer and autoimmune diseases without complex laboratory processing, ScienceDaily reported.
Current immune cell therapies, such as those relying on chimeric antigen receptor T cells approved by the U.S. Food and Drug Administration over the past decade, require extracting a patient’s blood, modifying cells in specialized facilities, and reinfusing them. This lengthy manufacturing chain increases time, expense, and operational complexity.
Researchers at the Massachusetts Institute of Technology developed a method to bypass external cell manipulation entirely. By delivering messenger RNA directly to natural killer cells in vivo through targeted fatty molecules, the team generated functional CAR NK cells capable of eliminating tumors and reversing autoimmune damage in animal models.
Nanoparticles Modify NK Cells to Attack Tumor Cells
"The manufacturing challenges with CAR NK cells are significant." The idea here is you can deliver a nanoparticle that will modify your own NK cells with a CAR construct and teach them to attack tumor cells,” said Daniel Anderson, a professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, as reported by ScienceDaily. Anderson is the senior author of the research published in Nature Biotechnology.”
Standard CAR T cell therapies present a major clinical hurdle when targeting diseases involving abnormal T cells. Because both the engineered therapy and the targeted malignant or autoreactive cells are T cells, the engineered cells often attack and destroy one another. Natural killer cells belong to a distinct lineage of lymphocytes, allowing them to target diseased T cells without triggering this internal fratricide.
“NK cells can treat these T cell malignancies — not only T cell cancer, but also T cell autoimmune diseases,” said Yuang Chen, an MIT postdoctoral researcher and lead author of the study. Alongside Chen, graduate students Julia Monkovic and Haseeb Mughal served as lead authors, with contributions from Robert Langer, MIT’s David H. Koch Institute Professor.
Lipid Nanoparticles Deliver Genetic Instructions
The MIT team constructed lipid nanoparticles designed to transport messenger RNA safely through the bloodstream. To ensure precise cellular tropism, the researchers coated the exterior of these nanoparticles with antibody fragments that bind specifically to surface receptors on natural killer cells.
Once the nanoparticle fuses with the targeted natural killer cell, the enclosed messenger RNA directs the cellular machinery to synthesize a chimeric antigen receptor. This newly expressed receptor equips the cell to recognize designated surface markers, such as CD19 on B cells or CD3 on T cells. Animal experiments demonstrated that the nanoparticles successfully modified roughly 80 percent of the targeted natural killer cell population in vivo.
In murine models of aggressive melanoma, three out of five animals treated with the targeted nanoparticles achieved complete tumor remission. When tested on humanized mice exhibiting T cell lymphoma, five successive nanoparticle injections completely eradicated the tumors. These results mirrored the therapeutic efficacy of conventionally manufactured CAR NK cells produced outside the living organism.
Reversing Autoimmune Hepatitis in Animal Models
The therapeutic utility of the lipid nanoparticle delivery system extended beyond oncology into immunology. Investigators evaluated the technology on an animal model of autoimmune hepatitis, a condition characterized by autoreactive T cells attacking hepatocytes, the primary functional cells of the liver.
Administering a single nanoparticle injection programmed the animals’ natural killer cells to recognize and destroy the harmful T cells driving the autoimmune response. Following the elimination of these autoreactive lymphocytes, the damaged liver tissue in the treated subjects regenerated and healed successfully.
“This study is an excellent example of the power of nano delivery systems and their ability to potentially treat cancer and other diseases,” Langer said.
| Therapeutic Approach | Manufacturing Location | Target Cell Type | Primary Advantage |
|---|---|---|---|
| Conventional CAR-T | Ex vivo (External Laboratory) | T Cells | Established FDA-approved track record for blood cancers |
| Conventional CAR-NK | Ex vivo (External Laboratory) | Natural Killer Cells | Avoids T-cell fratricide against T-cell malignancies |
| In Vivo mRNA Nanoparticles | In vivo (Directly Inside Patient) | Natural Killer Cells | Eliminates complex laboratory processing and reduces cost |
Clinical Translation and Future Pipeline
While the preclinical data demonstrate substantial tumor destruction and tissue repair in murine models, the technology has not yet advanced to human clinical trials, and no in vivo CAR NK cell therapies possess regulatory approval from agencies such as the FDA. The research team aims to adapt the nanoparticle platform to address other chronic autoimmune conditions driven by dysfunctional T cells, including multiple sclerosis and rheumatoid arthritis.
Financial support for the investigation was provided by Sanofi, the Marble Center for Cancer Nanomedicine, and a Koch Institute Support Grant originating from the National Cancer Institute.
Genetic Reprogramming Remains in Preclinical Research Phase
Because this genetic reprogramming technology remains in the preclinical research phase, it is not available for clinical administration outside of controlled trials. Patients undergoing treatment for hematologic malignancies or autoimmune disorders must rely on currently approved therapeutic regimens.
References
- Chen, Y., Monkovic, J., Mughal, H., Langer, R., and Anderson, D. In vivo reprogramming of natural killer cells using lipid nanoparticles. Nature Biotechnology.
- U.S. Food and Drug Administration (FDA). Approved Cellular and Gene Therapy Products.
- National Cancer Institute (NCI). CAR T Cells: Engineering Patients’ Immune Cells to Treat Cancer.
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