Project Summary Over 60% of cancer patients undergo radiation therapy during their disease process, which frequently leads to injury to surrounding healthy tissue and results in complications such as oral mucositis and proctitis. This normal tissue injury can cause severe morbidity and treatment discontinuation, resulting in potentially inferior tumor control. Attempts to reduce these side effects include systemic radioprotectants, tissue spacing technolo- gies, and radiation techniques, yet these methods are fraught with limitations like selectivity, severe hypotension, issues with spacer placement, and infection. As a result, there is a pressing need for innovative methods for effective radiation protection. To address this need, we propose to develop clinically deliverable RNA strategies for radiation protection, which facilitates the cell-specific targeted delivery of nucleic acids, enables sustained expression of extremophilic proteins for enhanced radioprotective capabilities, and ensures the therapy can be effectively and safely admin- istered into tissues. Our work aims to lay the groundwork for the use of nucleic acid-based therapies for radiation protection. By leveraging the protective qualities of extremophile proteins and developing new delivery methods, we aspire to reduce the impact of radiation-induced injuries, thereby enhancing patient outcomes and quality of life.

Project Narrative Most cancer patients will undergo radiation therapy at some point in their disease course, a treatment that frequently causes collateral injury to healthy tissue, leading to severe complications or even treatment discon- tinuation. Current methods of preventing this injury are wrought with challenges: 1) the inability to sustain radio- protection and maintain tumor cytotoxic effects simultaneously, and 2) side effects. In this proposal, we aim to develop a novel RNA strategy that delivers self-amplifying-RNAs coding for extremophile properties to tissues at risk for radiation-induced normal tissue injury.