Researchers at Northwestern University have developed a more effective therapeutic vaccine for HPV-related cancers by rearranging components in a DNA-based nanoparticle. This structural adjustment significantly enhances the immune system's ability to target and destroy tumors. The findings, published in Science Advances, highlight the importance of molecular arrangement in vaccine design.
Scientists at Northwestern University have demonstrated that the physical arrangement of components in a cancer vaccine can greatly influence its effectiveness. In a study published on February 11 in Science Advances, the team focused on therapeutic vaccines for cancers driven by the human papillomavirus (HPV), which causes most cervical cancers and an increasing share of head and neck cancers.
The vaccine is based on spherical nucleic acids (SNAs), a nanotechnology invented by Chad A. Mirkin, the George B. Rathmann Professor at Northwestern. Unlike traditional vaccines that mix antigens and adjuvants without precise structure—a method Mirkin calls the 'blender approach'—this design organizes elements at the nanoscale. The researchers tested variations where a fragment of an HPV protein, known as an antigen, was positioned differently within the SNA nanoparticle.
Three configurations were evaluated in humanized mouse models of HPV-positive cancer and in tumor samples from head and neck cancer patients. The most effective version displayed the antigen on the nanoparticle's surface, attached via its N-terminus. This led to up to eight times more interferon-gamma production by CD8 T cells, the immune system's key cancer fighters. In animal models, it slowed tumor growth and extended survival. In patient samples, it increased cancer cell killing by twofold to threefold.
'This effect did not come from adding new ingredients or increasing the dose,' said Dr. Jochen Lorch, a professor of medicine at Northwestern and medical oncology director for the Head and Neck Cancer Program. 'It came from presenting the same components in a smarter way. The immune system is sensitive to the geometry of molecules.'
The study underscores the emerging field of structural nanomedicine, which Mirkin pioneered. 'The promise of structural nanomedicine is being able to identify from the myriad possibilities the configurations that lead to the greatest efficacy and least toxicity,' Mirkin stated. 'In other words, we can build better medicines from the bottom up.'
Previous SNA-based vaccines have targeted melanoma, triple-negative breast cancer, colon cancer, prostate cancer, and Merkel cell carcinoma, with seven advancing to human trials. The team plans to apply these insights to refine earlier candidates and incorporate artificial intelligence to optimize designs. The research was supported by the National Cancer Institute and the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.
