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

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 signalto-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 referencedensity 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. Our code is available at https://github.com/xulabs/aitom.