Nanoparticle System Shows Promise for Delivering mRNA to Prevent Type 1 Diabetes, suggests study

Research on preventing type 1 diabetes often focuses on limiting the autoimmune response that destroys the body’s ability to produce its own insulin. A new technology developed by scientists at the University of Chicago takes a different approach, centered on preserving insulin-producing beta cells by giving them the ability to protect themselves.

In a new study published this week in Cell Reports Medicine, researchers showed how nanoparticles created with lipids can deliver mRNA molecules to beta cells and prompt them to express more PD-L1, a cell surface protein that helps evade the immune system. In experiments with both mouse and human beta cells, the nanoparticles successfully reached their target and triggered PD-L1 expression. The same approach also worked in a model where human beta cells were transplanted into mice.

“In this initial therapeutic proof of concept, we showed that we were able to deliver PD-L1 mRNA with our nanoparticle system, enable a delay in type 1 diabetes progression in mice, and also show potential translational relevance within human cells,” said Jacob Enriquez, PhD, a postdoctoral scholar at UChicago who led the study. “So not only have we provided a vehicle for delivery to beta cells, which is innovative and exciting, but we've also shown that they can produce PD-L1 for immune protection.”

Building on success of RNA delivery technology

Enriquez works in the lab of Raghu Mirmira, MD, PhD, Professor of Medicine, where they focus on finding treatments to increase insulin production. For the new study, they teamed up with Yun Fang, PhD, Professor of Medicine, and Zhengjie Zhou, PhD, a former postdoc at UChicago who jointly trained with Fang and Matthew Tirrell, PhD, the D. Gale Johnson Distinguished Service Professor Emeritus in the Pritzker School of Molecular Engineering. Their team specializes in developing nanoparticles to deliver therapeutic cargo to cells and tissues. In this case, Zhou, who is now at Temple University, created a nanoparticle made of four lipids that can encapsulate mRNA molecules, the same technology used in some COVID-19 vaccines.

This lipid nanoparticle contained mRNA instructions for the PD-L1 protein. PD-L1 is an immune system inhibitor that limits activity of T-cells and prevents autoimmune disease, inflammation, and damage to healthy tissues during infection. It is often co-opted by cancers to evade the immune system, which is why immunotherapy treatments are designed to block it.

“Nanomedicine approaches were central to the clinical success of RNA vaccines,” Fang said. “Our conceptual and technological advances establish a strong foundation for extending this paradigm to metabolic diseases through selective targeting of insulin-producing cells and, ultimately, other key cell types involved in type 1 diabetes.”

Precisely targeting beta cells

The team created two versions of the nanoparticles: one tagged with a peptide to target GLP-1 receptors on the surface of beta cells (the same receptor used by weight loss drugs like Ozempic and Wegovy), and one nanoparticle without the peptide. During in vitro testing, both versions were able to enrich PD-L1 expression in mouse and human cells, although the GLP-1 tagged version performed a little better for mice. The approach also worked in an experimental model where human islet cells were transplanted into mice before the nanoparticles were injected.

Ideally, such a treatment in humans would be delivered before full disease onset, while some beta cells are still functional to preserve insulin production. One of the big advantages of this approach is that both versions of the nanoparticles can target beta cells without affecting other cell types, thereby avoiding unintended results. The team also hopes to leverage them to deliver other therapeutic molecules and possibly add more surface peptides to target receptors on human beta cells more effectively.

“This is generating a new level of excitement, because now we're thinking about engineering beta cells with the knowledge we've accumulated over the years,” said Mirmira, who is also Director of the UChicago Diabetes Research and Training Center. “Going forward, it's a promising tool because we can target a specific cell type without harming other cells.”

Reference:

Enriquez, Jacob R. et al., Messenger RNA delivery to islet β cells using conjugated lipid nanoparticles, Cell Reports Medicine.