Lipid Nanoparticles Reprogram NK Cells Inside the Body to Fight Cancer and Autoimmune Disease

Engineered immune cells have transformed the treatment of certain blood cancers over the past decade, but the process of making them remains slow, laborious and extraordinarily expensive. Now, engineers at the Massachusetts Institute of Technology report a strategy that could collapse much of that complexity into a single injection. In a study published in Nature Biotechnology, the team describes lipid nanoparticles that deliver messenger RNA directly to natural killer cells inside the body, reprogramming them on the spot to hunt down cancerous T cells and T cells that have turned against the body’s own tissues. In mouse models, the approach drove complete remissions in an aggressive melanoma, eradicated T cell lymphoma tumors, and healed liver damage in autoimmune hepatitis, in some cases after just one dose.

The technique targets a long-standing bottleneck in cellular immunotherapy. Approved CAR T cell therapies, seven of which have been cleared by the U.S. Food and Drug Administration over the past ten years, all follow the same demanding recipe. Doctors draw blood from a patient, ship the sample to a specialized manufacturing facility, isolate the T cells, engineer them to express a chimeric antigen receptor, a synthetic protein that recognizes a specific target antigen, expand the engineered cells to sufficient numbers, and then infuse them back into the patient. Each step adds time, cost and logistical fragility, and the same challenges have carried over into efforts to build therapies around natural killer cells, a different branch of the immune system with its own distinct advantages.

Natural killer cells are innate immune cells that specialize in detecting and destroying stressed, infected or malignant cells, and they can be armed with chimeric antigen receptors just as T cells can. For one class of diseases, they hold a decisive edge over engineered T cells. When the therapeutic target is a T cell itself, whether a malignant T cell in lymphoma or an autoreactive T cell driving an autoimmune condition, CAR T cells run into a fundamental problem: T cells engineered to recognize T cell proteins can attack one another, depleting the therapy and undermining the treatment. Natural killer cells face no such fratricidal conflict, because they are a different cell type and can eliminate dysfunctional T cells without destroying their own kind.

NK cells can treat these T cell malignancies, not only T cell cancer but also T cell autoimmune diseases, the researchers note. Yet manufacturing large quantities of CAR NK cells outside the body poses many of the same difficulties as generating CAR T cells, and no CAR NK therapy has yet been approved by the FDA, although many groups are working toward that goal. The MIT team set out to remove the ex vivo manufacturing step entirely by generating CAR NK cells in vivo, inside the patient’s own body, without removing any cells. If a patient can simply receive an infusion of nanoparticles, the process would be dramatically simplified and the costs substantially reduced, the researchers say.

The delivery vehicle at the heart of the study is the lipid nanoparticle, the same class of fatty carrier that made mRNA vaccines possible. In this application, the particles encapsulate strands of messenger RNA encoding a chimeric antigen receptor, the instructions a cell needs to build the targeting protein on its own surface. Because the payload is mRNA rather than DNA, the reprogramming is transient: the NK cells produce the receptor for a limited period, which offers a built-in safety margin and allows dosing to be adjusted. The researchers designed the particles to carry receptors directed against specific antigens, including CD19, a protein found on B cells, and CD3, a protein found on T cells, including the autoreactive ones implicated in autoimmune hepatitis.

Getting the particles to the right cells is the other half of the engineering problem. Lipid nanoparticles administered systemically tend to be taken up by liver cells and other scavenging tissues rather than by circulating immune cells. To solve this, the MIT team coated the particles with antibody fragments that bind to receptors on the surface of NK cells, ensuring that the payload is delivered preferentially to the intended targets. When the particles were infused into mice, the researchers found that they successfully reprogrammed roughly 80 percent of the targeted NK cells, a strikingly high efficiency for an in vivo cell-engineering approach and one that suggests a meaningful fraction of a patient’s native NK population could be conscripted without any laboratory manipulation.

The therapeutic results in animal models spanned both halves of the team’s ambition: cancer and autoimmunity. In a mouse model of an aggressive form of melanoma, three of the five mice that received nanoparticles reprogramming their NK cells to target the cancer cells went into complete remission. In a humanized mouse model, one in which mice receive transfusions of human blood cells and transiently generate a human-like immune system, the researchers used the particles to treat T cell lymphoma. After five injections of the reprogramming nanoparticles, tumors were eradicated, and the outcome was comparable to what the team achieved with conventionally manufactured CAR NK cells, the kind produced by removing NK cells, engineering them in the lab and returning them to the animals.

The autoimmune experiments may prove the more novel contribution, since they demonstrate that in vivo reprogramming can be aimed at a self-destructive immune response rather than a tumor. Autoimmune hepatitis occurs when autoreactive T cells attack hepatocytes, the functional cells of the liver, progressively damaging the organ. When mice with the disease received nanoparticles encoding a receptor directed against those T cells, the autoreactive population was destroyed and the liver damage healed, with these effects observed after a single injection. The researchers hope engineered NK cells of this kind could eventually be applied to a broader range of autoimmune disorders driven by dysfunctional T cells, naming multiple sclerosis and rheumatoid arthritis as potential targets.

The work is an example of the power of nano delivery systems and their potential to treat cancer and other diseases, according to Robert Langer, the David H. Koch Institute Professor at MIT and a co-author of the study. The research was led by senior author Daniel Anderson, a professor in MIT’s Department of Chemical Engineering and a member of the Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science, together with lead authors Yuang Chen, Julia Monkovic and Haseeb Mughal. The study was funded by Sanofi, the Marble Center for Cancer Nanomedicine, and a Koch Institute Support Grant from the National Cancer Institute. Much work remains before the approach can be tested in patients, from confirming safety and dosing to demonstrating that the nanoparticles can efficiently reach NK cells in humans as they do in mice. But if the in vivo strategy translates, it would replace a weeks-long, facility-intensive manufacturing pipeline with a ready-to-infuse product, potentially widening access to engineered cell therapy far beyond the specialized centers that can currently offer it.

Subject of Research: In vivo reprogramming of natural killer cells with ligand-directed lipid nanoparticles for cancer and autoimmune disease immunotherapy

Article Title: Reprogrammed NK immune cells target cancer and autoimmune disorders

Article References: Reprogrammed NK immune cells target cancer and autoimmune disorders. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: natural killer cells, CAR NK cells, lipid nanoparticles, messenger RNA, immunotherapy, T cell lymphoma, autoimmune hepatitis, melanoma, MIT, Nature Biotechnology, cell therapy, nanomedicine