DNA Framework‐Ensembled Aptamers Enhance Fluid Stability in Circulating Tumor Cells Capture for Tumor Treatment Evaluation

Abstract The recognition and binding via receptor‐ligand interactions on cell membranes often weaken in complex environments, such as whole blood samples from cancer patients, making disease diagnosis and treatment evaluation unfavorable. Constructing multivalent ligands with sufficient fluid stability in complex environments remains a challenge. Herein, we develop a tetrahedral DNA framework (TDF) ensembled multivalent aptamers (TEA n , n = 1–3) with programmable ligands size, enabling efficient capture of circulating tumor cells (CTCs) and accurate monitoring of clinical treatment progress. The precisely structured TEA n ensures the size‐matching and cooperative hybridization with epithelial cell adhesion molecule (EpCAM) on cell membrane. Compared to traditional aptamer approach, the dissociation constants (K d ) of TEA 3 exhibits ∼20‐fold growth in serum due to its precise size and rigid DNA framework. This high‐affinity interaction significantly enhances capture efficiency by improving fluid stability of TEA n and magnetic beads complex in complex environment. In addition, this CTC detection strategy is applied for clinical tumor treatment evaluation and progress monitoring in liver cancer patient samples, achieving an accuracy of ∼83.3% in classifying patients as complete or partial responses (CR/PR). Overall, this strategy will strongly promote potential clinical application of DNA framework for cancer diagnosis and disease progression monitoring.