RNAGenesis: A Generalist Foundation Model for Functional RNA Therapeutics

作者：Zaixi Zhang, Ruofan Jin, Linlin Chao, Guangxue Xu, Yikun Zhang, Guowei Zhou, Di Yin, Yingqing Guo, Yaqi Fu, Yukang Yang, Kaixuan Huang, Xiaotong Wang, J Zhang, Yujie Yang, Qiang Yang, Zhao Xu, E Weinan, Ruhong Zhou, Xiaomin Zhang, Mengdi Wang, Le Cong · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.12.30.630826 · 被引用次数：14 · 研究领域：RNA and protein synthesis mechanisms、CRISPR and Genetic Engineering、RNA regulation and disease

ABSTRACT RNA molecules are central to gene regulation, catalysis, and molecular recognition, and offer broad opportunities for therapeutic applications. However, uncovering their complex sequence, structure, and function relationships, particularly for non-coding RNAs, remains a formidable challenge. Here, we introduce RNAGenesis , a Generalist RNA foundation model that integrates sequence representation, structural prediction, and de novo functional design within a single generative framework. Trained on diverse clustered non-coding RNAs, RNAGenesis leverages a BERT-style encoder, query-based latent compression, and a diffusion-guided decoder enhanced by inference-time alignment with gradient guidance and beam search strategies. Through comprehensive evaluations, RNAGenesis achieves state-of-the-art performance on 11 of 13 tasks in the BEACON benchmark and surpasses structure-aware models in inverse folding, 3D structure prediction, and de novo structure design. We further introduce RNATx-Bench , a dedicated benchmark for RNA therapeutics comprising over 100,000 experimentally validated sequences. RNAGenesis demonstrates strong predictive performance across ASOs, siRNAs, shRNAs, circRNAs, and untranslated region (UTR) variants. Furthermore, RNAGenesis enables functional RNA design, including aptamers targeting IGFBP3 and structurally constrained sgRNA scaffolds. Wet-lab validation confirms aptamer binding with K D values as low as 4.02 nM and up to 2.5-fold improvement in ed...