Polymer-Coated Nanoparticles Target and Clear Disseminated Ovarian Cancer

By pairing precision-engineered nanoparticles that can deliver IL-12 with 'checkpoint inhibitors', MIT scientists have found a way to accelerate the immune system's attack on ovarian cancer cells.

In mouse models, the study found that many of the animals' immune systems demonstrated recognition of the tumor cells five months after treatment. 

Cancer immunotherapy employs drugs that activate the immune cells of the body to target tumors, representing a hopeful strategy for addressing various forms of cancer. Nevertheless, it is not effective for certain tumors, such as ovarian cancer.

To address this limitation, researchers from MIT have developed new nanoparticles that can deliver IL-12, an immune-stimulating molecule, directly to ovarian tumors. When used alongside immunotherapy drugs called checkpoint inhibitors, IL-12 helps the immune system attack cancer cells. 

In a mouse model of ovarian cancer, researchers showed that this combination of treatments could eliminate metastatic tumors in over 80 % of the mice used. When the mice were injected with additional cancer cells to mimic tumor recurrence, the immune cells recognized the tumor proteins and successfully eliminated them again.

What’s really exciting is that we’re able to deliver IL-12 directly in the tumor space. And because of the way that this nanomaterial is designed to allow IL-12 to be borne on the surfaces of the cancer cells, we have essentially tricked the cancer into stimulating immune cells to arm themselves against that cancer.

Paula Hammond, Vice Provost for Faculty, Massachusetts Institute of Technology

Hammond and Darrell Irvine, a professor specializing in immunology and microbiology at the Scripps Research Institute, serve as the senior authors of the new study. The lead author of the paper is Ivan Pires, PhD ’24, who is currently a postdoctoral researcher at Brigham and Women’s Hospital. Their study was published in Nature Materials.

'Hitting the Gas'

Most tumors produce and release proteins that inhibit immune cells, resulting in a microenvironment that weakens the immune response. T cells are among the most effective agents for destroying tumor cells, but they are often hindered or obstructed by cancer cells, preventing them from attacking the tumor.

Checkpoint inhibitors are a treatment approved by the FDA, intended to remove these inhibitory effects on the immune system by eliminating the immune-suppressing proteins, thereby enabling T cells to attack tumor cells.

In certain cancers, such as specific forms of melanoma and lung cancer, alleviating these inhibitory effects is sufficient to stimulate the immune system to target cancer cells.

Conversely, ovarian tumors possess numerous mechanisms to suppress the immune system, often making checkpoint inhibitors alone inadequate to trigger an immune response.

The problem with ovarian cancer is no one is hitting the gas. So, even if you take off the brakes, nothing happens.

Ivan Pires, Postdoctoral Researcher, Brigham and Women’s Hospital

IL-12 provides a method to 'hit the gas' by enhancing T cells and other immune cells. However, substantial amounts of IL-12 are necessary to elicit a robust response, which can result in adverse effects stemming from widespread inflammation.

These adverse effects range from flu-like symptoms (fever, gastrointestinal problems, headaches, and fatigue) to more serious complications such as liver toxicity and cytokine release syndrome, which may result in death.

In a 2022 study, Hammond’s laboratory developed nanoparticles capable of delivering IL-12 directly to tumor cells, allowing for the administration of larger doses while minimizing the side effects associated with the drug's injection. However, these particles often released their payload in a single burst upon reaching the tumor, which impeded their ability to elicit a robust T cell response.

In the new study, the researchers altered the particles to facilitate a more gradual release of IL-12, spanning approximately one week. This was accomplished by employing a different chemical linker to attach IL-12 to the nanoparticles.

With our current technology, we optimize that chemistry such that there’s a more controlled release rate, and that allowed us to have better efficacy.

Ivan Pires, Postdoctoral Researcher, Brigham and Women’s Hospital

The particles are composed of small, fatty droplets referred to as liposomes, with IL-12 molecules affixed to their surface. In this research, the scientists employed a linker named maleimide to bind IL-12 to the liposomes. This linker exhibits greater stability compared to the one utilized in the earlier generation of particles, which was prone to cleavage by proteins present in the body, resulting in premature release.

The researchers apply a coating of poly-L-glutamate (PLG) to the particles, ensuring they arrive at their intended destination and facilitating their direct targeting of ovarian tumor cells. Upon reaching the tumors, the particles adhere to the surfaces of the cancer cells, where they slowly release their payload and stimulate adjacent T cells.

Disappearing Tumors

In experiments conducted on mice, the researchers demonstrated that the particles carrying IL-12 were capable of effectively recruiting and activating T cells that target tumors.

The cancer models used in these investigations are metastatic, meaning that tumors developed in the peritoneal cavity, which encompasses the surfaces of the intestines, liver, pancreas, and other organs, as well as the ovaries. Tumors were even observable in the lung tissues.

Initially, the researchers conducted tests on the IL-12 nanoparticles independently, demonstrating that this treatment successfully eradicated tumors in approximately 30 % of the mice. The team observed a notable rise in the quantity of T cells that gathered within the tumor microenvironment.

The researchers then administered the particles to mice in conjunction with checkpoint inhibitors. This dual treatment cured over 80 % of the mice. This was observed even when the researchers employed models of ovarian cancer that exhibit significant resistance to immunotherapy or to the conventional chemotherapy agents used for ovarian cancer.

Patients diagnosed with ovarian cancer typically undergo surgical intervention before chemotherapy. Though this approach is initially effective, any residual cancer cells are often able to grow into new tumors. Developing an immune memory of the tumor proteins may assist in mitigating the likelihood of such recurrences.

Researchers found that the immune system was able to recognize and kill tumor cells when the cured mice were re-injected with them five months after treatment. 

“We don’t see the cancer cells being able to develop again in that same mouse, meaning that we do have an immune memory developed in those animals,” said Pires.

The researchers are currently collaborating with MIT’s Deshpande Center for Technological Innovation to establish a company that they hope will further develop their nanoparticle technology. In a study released earlier this year, Hammond’s laboratory disclosed a novel manufacturing method that is expected to facilitate large-scale production of this specific type of nanoparticle.

The study received financial support from the National Institutes of Health, the Marble Center for Nanomedicine, the Deshpande Center for Technological Innovation, the Ragon Institute of MGH, MIT, and Harvard, as well as the Koch Institute Support (core) Grant provided by the National Cancer Institute.

Journal Reference:

Pires, S, I., et al. (2025) IL-12-releasing nanoparticles for effective immunotherapy of metastatic ovarian cancer. Nature Materials. doi.org/10.1038/s41563-025-02390-9