# Score-Based Matching with Target Guidance for Cryo-EM Denoising

arXiv: https://arxiv.org/abs/2604.17734 · HTML: https://mlsanity.com/paper/2604.17734/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 9 of its 27 references that are in the map.
- First posted on arXiv 20 Apr 2026.

## Builds on (most cited first, 9 of 9)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Elucidating the Design Space of Diffusion-Based Generative Models](https://mlsanity.com/paper/2206.00364/) (2022)
- [Noise2Noise: Learning Image Restoration without Clean Data](https://mlsanity.com/paper/1803.04189/) (2018)
- [Noise2Void - Learning Denoising from Single Noisy Images](https://mlsanity.com/paper/1811.10980/) (2018)
- [Positive-unlabeled convolutional neural networks for particle picking in cryo-electron micrographs](https://mlsanity.com/paper/1803.08207/) (2018)
- [AR-DAE: Towards Unbiased Neural Entropy Gradient Estimation](https://mlsanity.com/paper/2006.05164/) (2020)
- [Unsupervised Image Denoising with Score Function](https://mlsanity.com/paper/2304.08384/) (2023)
- [DRACO: A Denoising-Reconstruction Autoencoder for Cryo-EM](https://mlsanity.com/paper/2410.11373/) (2024)

## Abstract (arXiv)

Cryo-electron microscopy (cryo-EM) enables single-particle analysis of biological macromolecules under strict low-dose imaging conditions, but the resulting micrographs often exhibit extremely low signal-to-noise ratios and weak particle visibility. Image denoising is therefore an important preprocessing step for downstream cryo-EM analysis, including particle picking, 2D classification, and 3D reconstruction. Existing cryo-EM denoising methods are commonly trained with pixel-wise or Noise2Noise-style objectives, which can improve visual quality but do not explicitly account for structural consistency required by downstream analysis. In this work, we propose a score-based denoising framework for cryo-EM that learns the clean-data score to recover particle signals while better preserving structural information. Building on this formulation, we further introduce a target-guided variant that incorporates reference-density guidance to stabilize score learning under weak and ambiguous signal conditions. Rather than simply amplifying particle-like responses, our framework better suppresses structured low-frequency background, which improves particle--background separability for downstream analysis. Experiments on multiple cryo-EM datasets show that our score-based methods consistently improve downstream particle picking and produce more structure-consistent 3D reconstructions. Experiments on multiple cryo-EM datasets show that our methods improve downstream particle picking and produce more structure-consistent reconstructions.