Learning Crossmodal Interaction Patterns via Attributed Bipartite Graphs for Single-Cell Omics

Crossmodal matching in single-cell omics is essential for explaining biological regulatory mechanisms and enhancing downstream analyses. However, current single-cell crossmodal models often suffer from three limitations: sparse modality signals, underutilization of biological attributes, and insufficient modeling of regulatory interactions. These challenges hinder generalization in data-scarce settings and restrict the ability to uncover fine-grained biologically meaningful crossmodal relationships. Here, we present a novel framework which reformulates crossmodal matching as a graph classification task on Attributed Bipartite Graphs (ABGs). It models single-cell ATAC-RNA data as an ABG, where each expressed ATAC and RNA is treated as a distinct node with unique IDs and biological features. To model crossmodal interaction patterns on the constructed ABG, we propose $\text{Bi}^2\text{Former}$, a **bi**ologically-driven **bi**partite graph trans**former** that learns interpretable attention over ATAC–RNA pairs. This design enables the model to effectively learn and explain biological regulatory relationships between ATAC and RNA modalities. Extensive experiments demonstrate that $\text{Bi}^2\text{Former}$ achieves state-of-the-art performance in crossmodal matching across diverse datasets, remains robust under sparse training data, generalizes to unseen cell types and datasets, and reveals biologically meaningful regulatory patterns. This work pioneers an ABG-based approach for single-cell crossmodal matching, offering a powerful framework for uncovering regulatory interactions at the single-cell omics. Our code is available at: https://github.com/wangxiaotang0906/Bi2Former.