NovaRNA - InNOVAtive approach to optimize untraslated regions for next-generation mRNA vaccines.

State of the art
Cancer represents a leading cause of mortality worldwide, with several tumors evading immune detection despite expressing recognizable antigens. Therapeutic cancer vaccines aim to stimulate the immune system, particularly cytotoxic CD8⁺ T cells, to recognize and eliminate tumor cells. Among emerging strategies, mRNA-based vaccines offer a flexible platform for delivering tumor antigens.

Unmet medical need
Current mRNA-based therapeutics, including cancer vaccines, typically employ untranslated regions (UTRs) selected for their ability to enhance mRNA stability and translation efficiency across diverse cell types. However, these UTRs are not specifically optimized for antigen-presenting cells (APCs), where the primary goal is not just protein production, but effective antigen presentation, a key process to trigger a robust immune response, ensuring vaccines’ efficacy. Indeed, high levels of antigen translation do not guarantee effective presentation to CD8⁺ T-cells, as protein abundance poorly correlates with immunogenicity. Consequently, commonly used UTRs may induce suboptimal antigen presentation and limit activation of CD8⁺ cytotoxic T-cell responses, reducing vaccines’ therapeutic efficacy.

Solution
NovaRNA has developed a proprietary platform that redefines mRNA vaccine design by selecting and engineering 5′ and 3′ UTRs from genes naturally expressed at high levels in human tissues. Using a dual functional screening strategy, employing either eGFP-encoding mRNA to assess translation or antigen-encoding mRNA to measure MHC-I presentation, the platform identifies UTR pairs that not only boost protein expression but also enhance antigen presentation and downstream CD8⁺ T-cell responses. Furthermore, rational UTR engineering was found to reduce innate immunogenicity, lowering reactogenicity without relying on costly nucleoside modifications. The therapeutic relevance of these optimized UTRs was demonstrated by integrating them into an mRNA vaccine encoding a melanoma-associated antigen, which resulted in stronger antigen-specific CD8⁺ T-cell activation and improved survival in a murine melanoma model. This project was supported by the Italian Ministry of University and Research through the National Recovery and Resilience Plan (PNRR) funding (CN00000041/CN3).

Advantages
NovaRNA’s platform enables next-generation mRNA cancer vaccines characterized by:
• enhanced CD8⁺ T-cells activation
• reduced innate reactogenicity
• high translation efficiency
• simple and affordable production
• broad applicability across different antigens and disease models for prophylactic and therapeutic use.

IP asset
Patent application IT-102025000026428; co-owned by IEO and University of Milan.