# TRIDENT: A Trimodal Cascade Generative Framework for Drug and RNA-Conditioned Cellular Morphology Synthesis

arXiv: https://arxiv.org/abs/2511.18287 · HTML: https://mlsanity.com/paper/2511.18287/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 18 of its 51 references that are in the map.
- First posted on arXiv 23 Nov 2025.

## Builds on (most cited first, 18 of 18)

- [An Image is Worth 16x16 Words: Transformers for Image Recognition at Scale](https://mlsanity.com/paper/2010.11929/) (2020)
- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Denoising Diffusion Implicit Models](https://mlsanity.com/paper/2010.02502/) (2020)
- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Scalable Diffusion Models with Transformers](https://mlsanity.com/paper/2212.09748/) (2022)
- [Classifier-Free Diffusion Guidance](https://mlsanity.com/paper/2207.12598/) (2022)
- [Neural Discrete Representation Learning](https://mlsanity.com/paper/1711.00937/) (2017)
- [Improved Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2102.09672/) (2021)
- [GLIDE: Towards Photorealistic Image Generation and Editing with Text-Guided Diffusion Models](https://mlsanity.com/paper/2112.10741/) (2021)
- [Improved Techniques for Training GANs](https://mlsanity.com/paper/1606.03498/) (2016)
- [UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction](https://mlsanity.com/paper/1802.03426/) (2018)
- [Demystifying MMD GANs](https://mlsanity.com/paper/1801.01401/) (2018)
- [Adversarial Variational Bayes: Unifying Variational Autoencoders and Generative Adversarial Networks](https://mlsanity.com/paper/1701.04722/) (2017)
- [A Morphology Focused Diffusion Probabilistic Model for Synthesis of Histopathology Images](https://mlsanity.com/paper/2209.13167/) (2022)
- [How to Build the Virtual Cell with Artificial Intelligence: Priorities and Opportunities](https://mlsanity.com/paper/2409.11654/) (2024)
- [Predicting Cellular Responses to Novel Drug Perturbations at a Single-Cell Resolution](https://mlsanity.com/paper/2204.13545/) (2022)
- [CVAE-GAN: Fine-Grained Image Generation through Asymmetric Training](https://mlsanity.com/paper/1703.10155/) (2017)
- [A Diffusion Model Predicts 3D Shapes from 2D Microscopy Images](https://mlsanity.com/paper/2208.14125/) (2022)

## Abstract (arXiv)

Accurately modeling the relationship between perturbations, transcriptional responses, and phenotypic changes is essential for building an AI Virtual Cell (AIVC). However, existing methods typically constrained to modeling direct associations, such as Perturbation rightarrow RNA or Perturbation rightarrow Morphology, overlook the crucial causal link from RNA to morphology. To bridge this gap, we propose TRIDENT, a cascade generative framework that synthesizes realistic cellular morphology by conditioning on both the perturbation and the corresponding gene expression profile. To train and evaluate this task, we construct MorphoGene, a new dataset pairing L1000 gene expression with Cell Painting images for 98 compounds. TRIDENT significantly outperforms state-of-the-art approaches, achieving up to 7-fold improvement with strong generalization to unseen compounds. In a case study on docetaxel, we validate that RNA-guided synthesis accurately produces the corresponding phenotype. An ablation study further confirms that this RNA conditioning is essential for the model's high fidelity. By explicitly modeling transcriptome-phenome mapping, TRIDENT provides a powerful in silico tool and moves us closer to a predictive virtual cell.