Aptamers are short strands of RNA or DNA that can be synthesized and programmed to bind to cell-surface proteins—much like antibodies do—thereby playing an important role in diagnostics, imaging, and therapeutics. In fact, aptamers offer many advantages over antibodies, which are produced in living cells and are generally more complex to manufacture and modify. Unfortunately, developing aptamers has been hindered by low throughput and the lack of native protein conformations.

To resolve this problem, a research team led by Prof. TAN Weihong and Prof. WU Qin from the Hangzhou Institute of Medicine (HIM) of the Chinese Academy of Sciences has now developed a pioneering, multi-modal platform called SPARK-seq for the large-scale, systematic study of aptamer–target interactions. The research was published in Science on January 1.

SPARK-seq integrates CRISPR-based genetic perturbation, single-cell multi-omics, and sequence-based aptamer profiling. It 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 creates a direct link between ligand discovery and functional genomics, allowing for the identification of binders even for low-abundance or conformation-sensitive targets. 

Utilizing a multiplexed CRISPR knockout pool of 13 surface proteins and powered by the SPARTA computational pipeline, the researchers conducted an analysis of over 8,000 single cells. They identified 5,535 aptamer sequences targeting eight distinct proteins, including PTK7, CDCP1, and the PTPR family.

The ability to resolve kinetic profiles at scale is a key breakthrough of this platform. SPARK-seq was found to preferentially enrich 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 is a robust platform for aptomics, which will accelerate the rational design of high-specificity molecular tools and pave the way for advanced precision medicine and targeted drug delivery.