Engineering Metal Ion-Immunity Crosstalk for Metalloimmunotherapy - Engineering Metal Ion-Immunity Crosstalk for Metalloimmunotherapy Metal ions play essential roles in numerous immune processes through their unique structural, catalytic, and regulatory interactions with immune sensors, ion transporters, enzymes, and signaling pathways. Emerging studies have demonstrated that metal ions could modulate various immune processes for disease treatment. This lays the foundation for a new class of immunotherapy, which we dubbed “metalloimmunotherapy”. However, a comprehensive understanding of metal ion-immunity crosstalk and effective strategies for delivering metal ions to immune cells in vivo is still lacking in this field. The overarching goal of my lab is to understand how metal ions interact with immune system and to leverage advanced medicinal strategies to deliver metal ions to immune cells, modulating the immune system towards immunostimulatory or anti-inflammatory states for disease therapy. In this proposal, we aim to address the key knowledge gaps and technical challenges by systematically interrogating the metal ion-immunity interactions and developing specialized metal ion delivery systems to activate or regulate immune responses. In Part I, we identified extensive modulatory effects of metal ions on various immune pathways through a systematic high-throughput screening. Next, we will use gut as a window to investigate such metal ion-immunity crosstalk in vivo and validate our findings. This will elucidate the specific roles of metal ions in regulating gut immune cell functions and determine how these interactions contribute to gut diseases, including colon cancer and inflammatory bowel diseases (IBDs). In Part II, we proposed to engineer metal ion-immunity crosstalk to activate immune system for effective treatment of advanced colon cancer. We will develop novel coordination nanoparticles and hydrogels for effective delivery of metal ions and immune activators to amplify anti-tumor immune response. We will further establish the mechanism of action and improve the efficiency based on rational design. In Part III, we proposed to engineer metal ion-immunity crosstalk to regulate immune system in gut for treating IBDs. We will introduce two coordination nanoparticle-based strategies to target pathogenic immune cells in gut, inhibiting multiple IBD-related inflammatory processes and restoring immune balance. Successful completion of the proposed studies will provide groundbreaking insights of metal ion- immunity crosstalk and lay out a new framework for advancing metalloimmunotherapy. We will uncover previously unknown metal ion-immune interactions and their roles in health and disease. Furthermore, we will address key delivery challenges and biological gaps, paving the way for breakthrough treatments for advanced cancers and severe inflammatory or autoimmune diseases.
