mRNA-GPT: A Generative Model for Full-Length mRNA Design and Optimization

Abstract We introduce mRNA-GPT, a generative model for end-to-end full-length mRNA sequence design and optimization. Unlike existing approaches that optimize isolated regions, mRNA-GPT jointly optimizes across all three regions (5 ′ UTR, CDS, and 3 ′ UTR) to capture long-range sequence dependencies and cross-region regulatory interactions critical for therapeutic efficacy. The model is pre-trained on 30 million full-length natural mRNA sequences across diverse species and organisms, establishing a robust foundation for sequence generation. We employ Reinforcement Learning (RL), specifically Proximal Policy Optimization (PPO) with oracle-based reward signals, to directly and iteratively optimize target properties, such as half-life and translation efficiency. mRNA-GPT supports flexible generation modes: single regions (UTR or CDS alone), full-length sequences, or generation of any region conditioned on any other region. Through multi-objective optimization, mRNA-GPT achieves Pareto-optimal designs, i.e., solutions for which no single objective can be improved without degrading another, that balance competing properties without sacrificing performance on either objective. mRNA-GPT demonstrates superior design capabilities compared to state-of-the-art methods, achieving enhanced performance in 3 ′ UTR stability optimization, CDS translation rate enhancement, and comprehensive full-length sequence design.