Cell-surface proteins are critical therapeutic targets and vital to cellular communication, signaling, and homeostasis. However, developing high-affinity probes such as aptamers against these targets remain hindered by low throughput and lack of native protein conformations.

To address this challenge, a research team led by Prof. TAN Weihong and Prof. WU Qin from Hangzhou Institute of Medicine (HIM) of the Chinese Academy of Sciences (CAS) has developed a multi-modal platform which is called SPARK-seq. This platform integrates CRISPR-based genetic perturbation, single-cell multi-omics with sequence-based aptamer profiling, thereby pioneering the field of Aptomics for the large-scale, systematic study of aptamer-target interactions. The findings were published in Science on January, 1.

SPARK-seq enables high-throughput mapping of aptamers in their native cellular contexts by simultaneously profiling genetic perturbations, gene expression, and protein binding within a single cell. This strategy creates a direct link between ligand discovery and functional genomics, allowing for the identification of binders even for low-abundance or conformation-sensitive targets. To demonstrate this, the team utilized a multiplexed CRISPR knockout pool of 13 surface proteins. Their analysis, powered by the SPARTA computational pipeline, encompassed over 8,000 single cells. Ultimately, they identified 5,535 aptamer sequences targeting eight distinct proteins, including PTK7, CDCP1, and the PTPR family.

A key breakthrough of this platform is its ability to resolve kinetic profiles at scale. The data revealed that SPARK-seq preferentially enriches aptamers with slow dissociation rates, which is a vital trait for diagnostic and therapeutic efficacy. Furthermore, SPARTA’s deep learning module achieved 97% accuracy in predicting target-binding sequences and successfully generated functional variants with optimized kinetics.

By converting millions of binding events into high-dimensional sequencing data, SPARK-seq establishes a robust platform for Aptomics, which accelerates the rational design of high-specificity molecular tools and paves the way for advanced precision medicine and targeted drug delivery.