Antioxidant Double Hydrophilic Block Copolymer Polymersomes to Control T1D Autoimmunity

This project develops antioxidant polymer nanovesicles (polymersomes) for the treatment of diabetes. Type 1 Diabetes (T1D) is a chronic autoimmune disorder characterized by inflammatory destruction of insulin-producing β-cells in the pancreatic islets. Oxidative stress plays a crucial role in promoting inflammation within the islet microenvironment. The proposed research tests the hypothesis that antioxidant polymersomes can modulate redox signaling pathways and thereby reduce proinflammatory innate and adaptive immune responses. This research will address a critical gap in understanding how antioxidants regulate immunity while enabling the design of innovative antioxidant polymer vesicles for future immunomodulatory therapies. Insights from this research are aligned with the NSF Priority Area of Biotechnology, including the development of next-generation implants and tissue-engineered materials with improved biocompatibility and reduced immune-related complications. Ultimately, these advances can enhance the quality of life and long-term health outcomes for aging and immuno-compromised populations strengthening the Nation’s healthcare. The project's educational aims are to expand multidisciplinary science programs at UAB and KUMC and to provide students and scholars with training in biomaterials science and immunology. The collaborative experience will expand biomaterials research at both universities and will address the societal need for the development of safer, more effective antioxidant-responsive biomaterials to treat a broad range of immune-mediated disorders. The goal of this project is to design antioxidant, redox-responsive unilamellar polymer nanovesicles with programmable antioxidant functions and to evaluate their impact on innate and adaptive immune pathways to attenuate hyperinflammatory diabetogenic cell responses in T1D. The specific aims are as follows: (1) Develop the synthetic strategies of degradable double-hydrophilic temperature-sensitive diblock copolymers capable of an all-aqueous assembly into nanosized (100-300 nm) polymer vesicles (polymersomes), (2) Investigate the all-aqueous assembly of double-hydrophilic temperature-sensitive diblock copolymers into redox polymer nanovesicles and explore their degradability and response to reactive oxygen species (ROS), and (3) Study the effects of the antioxidant polymer nanovesicles on antigen-presenting cells (APCs)' shift between proinflammatory and anti-inflammatory states and dampening autoreactive T cell responses. This project advances understanding of the synthesis, hierarchical self-assembly, and reactive oxygen species (ROS)-triggered responses of antioxidant and redox-sensitive polymer nanovesicles and will clarify key mechanisms of redox regulation in immune responses. Specifically, the study will (i) establish synthetic routes to degradable double-hydrophilic, temperature-sensitive block copolymers and novel ROS-responsive antioxidant vesicles; (ii) elucidate how these nanovesicles selectively modulate proinflammatory responses in innate and adaptive immune cells; and (iii) define how they influence redox-regulated pathways governing immune-cell activation and proinflammatory chemokine/cytokine production. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.