Polymer-derived biomaterials for mRNA delivery to induce antigen-specific immune tolerance

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Project Summary The immune system protects people from pathogens. However, it sometimes generates abnormal immune reactions against harmless environmental antigens or patient’s own antigens, leading to allergy or autoimmune diseases, respectively. These hypersensitivity disorders affect millions of Americans and are life-threatening in severe conditions. Current therapeutic strategies often require lifelong treatment and/or broad immunosuppression, causing adverse effects. The induction of antigen-specific immune tolerance is a promising strategy to treat hypersensitivity without compromising immune protection because this strategy either specifically eliminate the disease-related immune cells or restrains their hypersensitive response, leaving the immune system intact. The tolerance may last lifelong once established. Although progress has been made in this area, technologies that induce efficient antigen-specific immune tolerance remain to be developed. The key to success in tolerance induction is the precise modulation of targeted immune cells. Compared to small drug molecules, a set of proteins translated from delivered messenger RNAs (mRNAs) in immune cells can work coordinately to transform the cells in a more precise manner. The success of COVID-19 mRNA vaccines has validated mRNA delivery as a platform for antigen-specific immune stimulation. However, mRNA delivery for inducing immune tolerance, an opposite effect as immune stimulation, has not been established. This is because most reported mRNA delivery nanocarriers cause inflammatory response and/or cannot target the right antigen- presenting cells (APCs) to initiate the process of tolerance induction. We have recently shown that our polymeric nanoparticle could efficiently target liver sinusoidal endothelial cells (LSECs), which are a type of APCs naturally helping the immune system maintain tolerance. We hypothesize that nanocarriers derived from this polymeric nanoparticle can co-deliver antigens and mRNAs encoding tolerogenic proteins to LSECs to induce antigen- specific immune tolerance. In our preliminary study, we demonstrated that such a nanocarrier can deliver mRNA to LSECs in mice for protein translation after systemic administration. We also demonstrated that the nanocarrier loaded with an antigen can inhibit the antigen-specific T cells from being restimulated after in vivo treatment of mice. We will test our hypothesis by 1) evaluating diverse nanocarrier formulations encapsulating antigen and mRNA in vitro; 2) investigating the biodistribution of selected nanocarriers and their tolerogenic potential in vivo; 3) demonstrating nanocarrier efficacy in animal disease models and elucidating the mechanism. Our proposed study is expected to have a broad scientific and societal impact by achieving antigen-specific tolerance via mRNA delivery.