Objective
The objective of this project is to develop a reliable method for delivering protective genetic therapies directly to insulin-producing β cells. This delivery system is designed to increase β-cell resilience, reduce harmful stress signals, and limit immune-mediated damage before diabetes fully develops. The long-term goal is to enable treatments that preserve β-cell function rather than replacing insulin after β cells are lost.
Background Rationale
Research over the past decade has shown that β-cell stress and inflammation occur early in T1D, even before immune cells fully infiltrate the pancreas. These early changes make β cells more visible and vulnerable to immune attack. Many promising therapies could reduce this stress or improve β-cell survival, but they cannot be used effectively because there is no way to deliver them specifically to β cells. Lipid nanoparticles offer a solution. They can carry RNA-based medicines that instruct cells to produce protective proteins or turn down damaging pathways. However, without targeting, these particles distribute broadly throughout the body. This project builds on recent advances to adapt LNP technology so that LNPs preferentially deliver their cargo to β cells, including human β cells, creating a foundation for more precise and safer therapies for T1D.
Description of Project
T1D develops when the immune system inappropriately attacks insulin-producing β cells in the pancreas. Long before diabetes is diagnosed, β cells experience inflammation and stress that make them more vulnerable to immune destruction. Once β cells are lost, they cannot be replaced, and lifelong insulin therapy becomes necessary. Current treatments manage blood glucose but do not prevent the underlying loss of β cells. This project addresses a central barrier in diabetes research: the inability to deliver protective therapies directly to β cells without affecting other tissues. The work centers on lipid nanoparticles (LNPs), tiny lipid-based particles that can safely deliver genetic material into cells. LNPs have already been used successfully in humans, including in mRNA vaccines, but they have not been optimized to target β cells. This research develops LNPs that preferentially deliver therapeutic RNA molecules to β cells. These RNA molecules can either increase the production of protective proteins or reduce harmful stress pathways within the cell. In parallel, short targeting peptides will be identified that help guide nanoparticles specifically to β cells, particularly human β cells. By testing these approaches in human islets donated for research and in advanced mouse models, this work establishes a platform that could support new therapies designed to preserve β cells and delay or prevent T1D.
Anticipated Outcome
This research is expected to establish a platform that delivers therapeutic RNA molecules directly to β cells with minimal effects on other tissues. The studies will define specific genetic instructions that most effectively reduce β-cell stress and immune vulnerability and identify targeting strategies that work in human β cells. These outcomes will provide a clear path toward developing β-cell–focused treatments that slow or prevent disease progression.
Relevance to T1D
T1D remains a disease without therapies that protect β cells before they are destroyed. This project directly addresses that gap by developing technology that delivers treatment to the cells most affected by the disease. By preserving β cells earlier in the disease process, this work supports a shift from managing diabetes after onset to intervening before irreversible damage occurs. The focus on human β cells increases the likelihood that these findings can translate into future clinical trials and, ultimately, new treatment options for people at risk for T1D.