Multi-Objective-Guided Generative Design of mRNA with Therapeutic Properties

Sawan Patel, Sophia Tang, Yinuo Zhang, Pranam Chatterjee, Sherwood Yao

Keywords: mrna, diffusion, design, therapeutics

TL;DR: Multi-objective-guided diffusion for generation of mRNA transcripts optimized across several therapeutic properties.

Abstract: Therapeutic mRNA design requires simultaneous optimization of multiple competing properties, including stability, translation efficiency, and protein expression—a challenge that current single-objective approaches struggle to address systematically. We introduce mRNA generation via Unrolled Trajectories and Informed Latent UpdateS (mRNAutilus), the first multi-objective guided generative model for simultaneous mRNA codon optimization and de novo design of untranslated region (UTR) sequences. mRNAutilus combines a Masked Diffusion Model (MDM) trained on 6 million evolutionary-scale mRNA sequences with Monte Carlo Tree Search to guide generation toward Pareto-optimal solutions across multiple therapeutic properties. As objective functions, we use the latent mRNAutilus embeddings to train classifiers for predicting half-life, ribosome profiling, and translation rate. Guided by our classifiers, we demonstrate that mRNAutilus successfully generates diverse, high-quality mRNA sequences with enhanced properties compared to natural sequences while preserving coding regions for therapeutic applications, establishing a new paradigm for rational mRNA design.

Submission Number: 28