New “CRYSTAL” Nanoparticles Unlock Safer, Stronger Cancer Immunotherapy

Media Contact: Lindsay Groth, Executive Director of Marketing and Communications, [email protected]

[Ann Arbor, Michigan] – Researchers at the University of Michigan and the University of Texas M.D. Anderson Cancer Center have developed a new type of nanoparticle therapy that could make cancer immunotherapy safer and more effective. The study, published May 7 in Science, introduces a platform called CRYSTAL that helps activate the body’s immune system to better fight cancer.

Preclinical studies show that CRYSTAL nanoparticles spark a powerful immune response that reduces or eliminates tumors—even large, advanced ones—without side effects like inflammation and weight loss, the study shows. 

The human immune system has natural tools to recognize and destroy cancer cells. One important pathway, called cGAS–STING, acts like an alarm system—detecting danger and triggering responses that help the body attack tumors. Scientists have long tried to harness this pathway for cancer treatment, but it has been difficult to use. Many STING‐activating agents overstimulate the immune response, causing acute inflammation. Others are unstable with short half-lives, so they must be injected directly into tumors, limiting their use.

“While the STING pathway is very powerful, turning it on safely in patients has been a major challenge,” said senior author James Moon, PhD, Chair and J. G. Searle Professor of Pharmaceutical Sciences at the University of Michigan College of Pharmacy. “We wanted to find a way to strongly activate the immune system without causing harmful side effects.”

To solve this problem, the team developed CRYSTAL, short for Crystal-like STING-Activating nanoassemblies. Researchers used manganese, a naturally occurring metal, to organize small immune-activating molecules into tiny, highly ordered particles. These particles are then coated with a fatty layer so they can travel safely through the bloodstream.

CRYSTAL produced strong, sustained immune activation at doses far lower than those required for conventional approaches. The team tested the nanoparticle across multiple tumor models, including advanced triple-negative breast cancer in vivo.

Importantly, CRYSTAL demonstrated anti-tumor activity without triggering a cytokine storm, which causes severe inflammation seen with other forms of immunotherapy. “We are achieving immune activation without systemic immune inflammation,” Moon said. “This is the first time we’re seeing such responses. We’re very excited about that.”

The researchers believe this work represents a new way of thinking about medicine design and the next generation of immunotherapies. “Our findings show that how a drug is built can be just as important as what it is made of,” said first author Xingwu Zhou, a graduate student in Pharmaceutical Sciences at the College of Pharmacy. “By arranging these molecules in a precise way, we can change how they behave in the body.”

“This work highlights how nutritional elements can be harnessed to fine-tune the magnitude of type-I interferon activation, a primary defense system evolutionarily conserved from humans to sea urchins,” said Yu Leo Lei, DDS, PhD, a longtime collaborator formerly at the University of Michigan School of Dentistry who is now Associate Professor of Head and Neck Surgery at The University of Texas MD Anderson Cancer Center. Lei’s group has made seminal contributions to the fundamental understanding of how metabolism and nutritional elements regulate the STING-IFN-I pathway and to the development of critical, high-fidelity head and neck squamous cell carcinoma models to test the efficacy of CRYSTAL. 

The findings result from a five-year collaboration among almost 30 researchers from the University of Michigan College of Pharmacy, Medical School, School of Dentistry, College of Engineering, the Center for Advanced Models for Translational Sciences and Therapeutics at Michigan State University, and UT MD Anderson. Funding from the National Institute of Dental and Craniofacial Research (NIDCR), the National Cancer Institute (NCI), the UM Rogel Cancer Center, and UT MD Anderson supported the work. The project was one of five funded by the Frankel Innovation Initiative at Michigan Medicine.

The CRYSTAL technology has been licensed to Saros Therapeutics and is advancing toward clinical development. In addition to improving cancer treatments, researchers believe this approach may also be applied to other immune-related diseases.

________________

About the College

The University of Michigan College of Pharmacy has been leading at pharmacy’s edge for 150 years. The first and oldest pharmacy school at a state university, the College — currently ranked #3 in the nation — has and continues to shape education in the field. Its faculty are internationally recognized and are innovators in drug discovery, development and delivery, precision pharmacotherapy, outcomes research, and clinical practice. More than 5,000 alumni are enhancing patient care and outcomes from the bench to the bedside, in boardrooms and communities, government agencies, and within healthcare companies.