A new approach to cancer vaccine design, focusing on the structure of the vaccine itself rather than simply its components, is showing promising results in preclinical models of HPV-driven tumors. Researchers at Northwestern University have discovered that subtly altering the arrangement of a single cancer-targeting peptide within a spherical nucleic acid (SNA) vaccine can dramatically enhance the immune system’s ability to attack tumors.
The findings, , 2026, published in the journal Science Advances, build upon a growing field called “structural nanomedicine,” pioneered by Northwestern’s Chad A. Mirkin. This field centers on the idea that the physical arrangement of molecules within a medicine can be as important as the molecules themselves.
Beyond the ‘Blender Approach’
Traditional vaccine development often relies on what Mirkin describes as a “blender approach” – simply mixing antigens (molecules from the tumor) with adjuvants (molecules that stimulate the immune system) and injecting the resulting cocktail. While effective, this method lacks precise control over how the immune system interacts with the vaccine components.
“If you look at how drugs have evolved over the last few decades, we have gone from well-defined small molecules to more complex but less structured medicines,” Mirkin explained. “The COVID-19 vaccines are a beautiful example — no two particles are the same. While very impressive and extremely useful, we can do better, and, to create the most effective cancer vaccines, we will have to.”
Structural nanomedicine, in contrast, deliberately organizes antigens and adjuvants into optimal configurations using SNAs – nanoscale structures that naturally enter and stimulate immune cells. This precise organization appears to significantly boost the vaccine’s potency and reduce potential toxicity.
HPV Vaccine Shows Enhanced Tumor Control
The Northwestern team focused on cancers caused by the human papillomavirus (HPV), which is responsible for the majority of cervical cancers and a growing number of head and neck cancers. Existing HPV vaccines are preventative, protecting against initial infection, but do not treat established cancers.
The researchers designed several therapeutic vaccines aimed at training the immune system’s CD8 “killer” T cells to recognize and destroy HPV-positive cancer cells. Each vaccine particle contained a nanoscale lipid core, immune-activating DNA, and a fragment of an HPV protein found in tumor cells. The key difference between the vaccine versions was the placement and orientation of this HPV-derived peptide fragment on the particle’s surface.
Three designs were tested: one where the fragment was hidden inside the nanoparticle, and two where it was attached to the surface, either through its N-terminus or C-terminus – a subtle change that can influence how immune cells process the antigen. The vaccine displaying the antigen on the surface, attached via its N-terminus, consistently outperformed the others.
This optimized vaccine triggered a significantly stronger immune response, with killer T cells producing up to eight times more interferon-gamma, a crucial signal for anti-tumor activity. In humanized mouse models of HPV-positive cancer, tumor growth slowed considerably. Importantly, the vaccine demonstrated increased cancer cell killing – two to threefold – in samples taken from patients with HPV-positive cancers.
“This effect did not come from adding new ingredients or increasing the dose,” said Dr. Jochen Lorch, a professor of medicine at Northwestern University Feinberg School of Medicine and medical oncology director of the Head and Neck Cancer Program at Northwestern Medicine. “It came from presenting the same components in a smarter way. The immune system is sensitive to the geometry of molecules. By optimizing how we attach the antigen to the SNA, the immune cells processed it more efficiently.”
A Blueprint for Future Vaccine Development
The success of this approach has broader implications for cancer vaccine development. Mirkin and his team have already applied structural nanomedicine to vaccines targeting melanoma, triple-negative breast cancer, colon cancer, prostate cancer, and Merkel cell carcinoma, all with promising preclinical results. Seven SNA drugs are currently in human clinical trials for various diseases, and SNAs are already used in over 1,000 commercial products.
Looking ahead, Mirkin plans to revisit previously promising vaccines that failed to generate strong enough immune responses in patients. He believes that by optimizing the nanoscale architecture of these vaccines, they can be “restructured and transformed into potent medicines.” He also envisions a future where artificial intelligence will accelerate vaccine design by rapidly identifying the most effective structural configurations.
“This approach is poised to change the way we formulate vaccines,” Mirkin said. “We may have passed up perfectly acceptable vaccine components simply because they were in the wrong configurations. We can go back to those and restructure and transform them into potent medicines. The whole concept of structural nanomedicines is a major train roaring down the tracks. We have shown that structure matters — consistently and without exception.”
The study was supported by the National Cancer Institute, the Lefkofsky Family Foundation, and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
