Deep generative optimization of mRNA codon sequences for enhanced mRNA translation and therapeutic efficacy
Yupeng Li, Fan Wang, Jiaqi Yang, Zirong Han, Lin‐Feng Chen, Wenbing Jiang, Hao Zhou, Tong Li, Zehua Tang, Jianxiang Deng, Xin He, Gao‐Feng Zha, Zhaoyu Hu, Yong Hu, Linping Wu, Changyou Zhan, Caijun Sun, Yao He, Zhi Xie
Abstract
Messenger RNA (mRNA) therapeutics show immense promise, but their efficacy is limited by suboptimal protein expression. Here, we present RiboDecode, a deep learning framework that generates mRNA codon sequences for enhanced mRNA translation. RiboDecode introduces several advances, including direct learning from large-scale ribosome profiling data and generative exploration of a large sequence space. In silico analysis demonstrates RiboDecode’s robust predictive accuracy for unseen genes and cellular environments. In vitro experiments showed substantial improvements in protein expression, significantly outperforming past methods. In addition, RiboDecode enables mRNA design with consideration of cellular context and demonstrates robust performance across different mRNA formats, including m1Ψ-modified and circular mRNAs, an important feature for mRNA therapeutics. In vivo mouse studies showed that optimized influenza hemagglutinin mRNAs induce ten times stronger neutralizing antibody responses against influenza virus compared to the unoptimized sequence. In an optic nerve crush model, optimized nerve growth factor mRNAs achieve equivalent neuroprotection of retinal ganglion cells at one-fifth the dose of the unoptimized sequence. Collectively, RiboDecode represents a paradigm shift from rule-based to a data-driven, context-aware approach for mRNA therapeutic applications, enabling the development of more potent and dose-efficient treatments. Messenger RNA therapeutics hold great promise but are limited by suboptimal protein expression. Here, the authors develop RiboDecode, a deep learning framework that generates optimized mRNA codon sequences to significantly enhance translation efficiency and therapeutic efficacy in both vaccines and protein replacement therapies.