Researchers have discovered that reconstitution of a single cancer-targeting peptide within a globular nucleic acid vaccine dramatically increases the immune system’s ability to attack HPV-induced tumors.
Over the past decade, scientists have northwestern university They discovered a new principle in vaccine design. That is, performance depends not only on the components used, but also on their structure.
After proving this concept in multiple studies, the team applied it to one of the most challenging targets in cancer treatment. tumor It is caused by the human papillomavirus (HPV). in new researchThey discovered that by systematically altering the orientation and placement of peptides that target a single cancer, they could generate vaccine formulations that enhance the immune system’s ability to attack tumors.
Building a better vaccine from scratch
The researchers first designed the vaccine in the form of spherical nucleic acids (SNAs), globular structures of DNA that naturally enter and stimulate immune cells. We then intentionally rearranged the components of SNA in multiple ways and tested each version in humanized animal models of HPV-positive cancers and patient-derived head and neck tumor samples.
One design consistently outperformed the rest, shrinking tumors, extending animal survival, and producing more highly active cancer-killing T cells.
One design consistently outperformed the rest, shrinking tumors, extending animal survival, and producing more highly active cancer-killing T cells. The findings highlight how subtle changes in the arrangement of components can determine whether a therapeutic nanovaccine weakly activates the immune system or produces a strong tumor-killing response.
This insight is the basis of the emerging field of “structural nanomedicine,” a term coined by SNA inventor Chad A. Mirkin, director of the Northwestern International Nanotechnology Institute.
“There are thousands of variables in a large, complex drug that define a vaccine,” said Mirkin, who led the study. “The potential of structural nanomedicine is that we can identify, among countless possibilities, the configurations that provide the most efficacy and the least toxicity. In other words, we can build better medicines from the bottom up.”
Artistic interpretation of spherical nucleic acid (SNA) nanoparticles carrying CpG adjuvant DNA that interacts with HPV antigen (E7₁₁–₁₉) and scavenger receptor A to promote cellular internalization. HPV antigen presentation and N-terminal orientation on N-HSNA enhances antigen-specific CD8+ T cell responses and antitumor activity. Credit: Image created by Connor Forsyth and Jake Cohen of Merkin Research Group/Northwestern University.
From blender approach to precision design
Traditional vaccine approaches often mix antigens and adjuvants into a simple cocktail before injection. Mirkin calls this a “blender approach,” where the components are unstructured.
“If you look at how medicines have evolved over the past few decades, we’ve gone from small, well-defined molecules to drugs that are more complex but have less well-defined structures,” Mirkin explained. “The COVID-19 vaccine is a beautiful example. No two particles are the same. It’s very impressive and very useful, but we can do even better. We need to do that if we are to develop the most effective cancer vaccines.”
Mirkin’s lab has shown that organizing antigens and adjuvants into precise configurations improves efficacy and reduces toxicity compared to unstructured mixtures. The research team has applied this approach to SNAs targeting melanoma, triple-negative breast cancer, colon cancer, prostate cancer, and Merkel cell carcinoma, with seven SNA drugs already in human trials and more than 1,000 commercial applications.
A smarter immune attack against HPV cancer
HPV causes most cervical cancers and is increasing in head and neck cancers. Current vaccines prevent infection but cannot treat existing tumors.
HPV causes most cervical cancers and is increasing in head and neck cancers.
The new vaccine was designed to train CD8 “killer” T cells to recognize and destroy HPV-positive cancer cells. Each particle contained the same nanoscale lipid core, immune activation DNA, and short HPV protein fragments. Only the location and orientation of the fragments differed.
“This effect was not caused by adding new ingredients or increasing the dose,” said co-leader Dr. Jochen Loch. “It comes from presenting the same components in a smarter way. The immune system is sensitive to the shape of the molecule, and by optimizing the way the antigen is attached to the SNA, we now allow immune cells to process the antigen more efficiently.”
The optimally constructed vaccine caused up to eight times more interferon gamma production, slowed tumor growth in humanized mice, and killed two to three times more cancer cells in patient tumor samples.
The future of vaccine design
Professor Mirkin will revisit previously failed vaccines and show that fine-tuning nanoscale structures can turn weak formulations into powerful treatments. Artificial intelligence could accelerate this process and help identify the most effective structures among an almost infinite number of combinations.
“This approach is poised to change the way vaccines are prescribed,” Mirkin said. “We may have missed perfectly acceptable vaccine components simply because they were configured incorrectly. We can go back and reassemble them and turn them into powerful medicines. The whole concept of structural nanomedicine is like a main train roaring down the tracks. We have consistently and without exception shown that structure matters.”