# Latent Diffusion Models for Controllable RNA Sequence Generation

arXiv: https://arxiv.org/abs/2409.09828 · HTML: https://mlsanity.com/paper/2409.09828/

## Key facts

- Cited by 4 papers in the map (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 80 of its 136 references that are in the map.
- First posted on arXiv 15 Sep 2024.

## Placed in

- Diffusion models / [Flow matching, time series and science](https://mlsanity.com/diffusion/flow-matching-time-series-and-science/)

## Builds on (most cited first, 30 of 80)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [Deep Residual Learning for Image Recognition](https://mlsanity.com/paper/1512.03385/) (2015)
- [BERT: Pre-training of Deep Bidirectional Transformers for Language Understanding](https://mlsanity.com/paper/1810.04805/) (2018)
- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [High-Resolution Image Synthesis with Latent Diffusion Models](https://mlsanity.com/paper/2112.10752/) (2021)
- [GPT-4 Technical Report](https://mlsanity.com/paper/2303.08774/) (2023)
- [Exploring the Limits of Transfer Learning with a Unified Text-to-Text Transformer](https://mlsanity.com/paper/1910.10683/) (2019)
- [LLaMA: Open and Efficient Foundation Language Models](https://mlsanity.com/paper/2302.13971/) (2023)
- [RoBERTa: A Robustly Optimized BERT Pretraining Approach](https://mlsanity.com/paper/1907.11692/) (2019)
- [Llama 2: Open Foundation and Fine-Tuned Chat Models](https://mlsanity.com/paper/2307.09288/) (2023)
- [Denoising Diffusion Implicit Models](https://mlsanity.com/paper/2010.02502/) (2020)
- [Score-Based Generative Modeling through Stochastic Differential Equations](https://mlsanity.com/paper/2011.13456/) (2020)
- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Hierarchical Text-Conditional Image Generation with CLIP Latents](https://mlsanity.com/paper/2204.06125/) (2022)
- [BLIP-2: Bootstrapping Language-Image Pre-training with Frozen Image Encoders and Large Language Models](https://mlsanity.com/paper/2301.12597/) (2023)
- [BART: Denoising Sequence-to-Sequence Pre-training for Natural Language Generation, Translation, and Comprehension](https://mlsanity.com/paper/1910.13461/) (2019)
- [Classifier-Free Diffusion Guidance](https://mlsanity.com/paper/2207.12598/) (2022)
- [Adding Conditional Control to Text-to-Image Diffusion Models](https://mlsanity.com/paper/2302.05543/) (2023)
- [RoFormer: Enhanced Transformer with Rotary Position Embedding](https://mlsanity.com/paper/2104.09864/) (2021)
- [Flamingo: a Visual Language Model for Few-Shot Learning](https://mlsanity.com/paper/2204.14198/) (2022)
- [Imagen Video: High Definition Video Generation with Diffusion Models](https://mlsanity.com/paper/2210.02303/) (2022)
- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [Diffusion Posterior Sampling for General Noisy Inverse Problems](https://mlsanity.com/paper/2209.14687/) (2022)
- [PaLM 2 Technical Report](https://mlsanity.com/paper/2305.10403/) (2023)
- [Scaling Laws for Reward Model Overoptimization](https://mlsanity.com/paper/2210.10760/) (2022)
- [Planning with Diffusion for Flexible Behavior Synthesis](https://mlsanity.com/paper/2205.09991/) (2022)
- [Diffusion-LM Improves Controllable Text Generation](https://mlsanity.com/paper/2205.14217/) (2022)
- [Training Diffusion Models with Reinforcement Learning](https://mlsanity.com/paper/2305.13301/) (2023)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [eDiff-I: Text-to-Image Diffusion Models with an Ensemble of Expert Denoisers](https://mlsanity.com/paper/2211.01324/) (2022)

## Built on by (most cited first, 4 of 4)

- [Efficient Diffusion Models: A Survey](https://mlsanity.com/paper/2502.06805/) (2025)
- [Structure-based RNA Design by Step-wise Optimization of Latent Diffusion Model](https://mlsanity.com/paper/2601.19232/) (2026)
- [Manifold Aware Denoising Score Matching (MAD)](https://mlsanity.com/paper/2603.02452/) (2026)
- [Property-Isometric Variational Autoencoders for Sequence Modeling and Design](https://mlsanity.com/paper/2509.14287/) (2025)

## Abstract (arXiv)

This work presents RNAdiffusion, a latent diffusion model for generating and optimizing discrete RNA sequences of variable lengths. RNA is a key intermediary between DNA and protein, exhibiting high sequence diversity and complex three-dimensional structures to support a wide range of functions. We utilize pretrained BERT-type models to encode raw RNA sequences into token-level, biologically meaningful representations. A Query Transformer is employed to compress such representations into a set of fixed-length latent vectors, with an autoregressive decoder trained to reconstruct RNA sequences from these latent variables. We then develop a continuous diffusion model within this latent space. To enable optimization, we integrate the gradients of reward models--surrogates for RNA functional properties--into the backward diffusion process, thereby generating RNAs with high reward scores. Empirical results confirm that RNAdiffusion generates non-coding RNAs that align with natural distributions across various biological metrics. Further, we fine-tune the diffusion model on mRNA 5' untranslated regions (5'-UTRs) and optimize sequences for high translation efficiencies. Our guided diffusion model effectively generates diverse 5'-UTRs with high Mean Ribosome Loading (MRL) and Translation Efficiency (TE), outperforming baselines in balancing rewards and structural stability trade-off. Our findings hold potential for advancing RNA sequence-function research and therapeutic RNA design.