Chen Yirong, Li Fan, Zhang Shuyang, Liu Feng, Mao Chenzhou, Li Min, Jiang Jinhua, Zhang Yueyue, Fan Chunhai, Zuo Xiaolei
Institute of Molecular Medicine, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
Angew Chem Int Ed Engl. 2025 Jun 10;64(24):e202425252. doi: 10.1002/anie.202425252. Epub 2025 Mar 10.
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 = 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 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) of TEA 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 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.
通过细胞膜上的受体 - 配体相互作用进行识别和结合在复杂环境中往往会减弱，例如癌症患者的全血样本，这不利于疾病诊断和治疗评估。构建在复杂环境中具有足够流体稳定性的多价配体仍然是一个挑战。在此，我们开发了一种四面体DNA框架（TDF）组装的多价适体（TEA，n = 1 - 3），其配体大小可编程，能够有效捕获循环肿瘤细胞（CTC）并准确监测临床治疗进展。精确构建的TEA确保了与细胞膜上上皮细胞粘附分子（EpCAM）的大小匹配和协同杂交。与传统适体方法相比，由于其精确的大小和刚性DNA框架，TEA的解离常数（K）在血清中显示出约20倍的增长。这种高亲和力相互作用通过提高TEA与磁珠复合物在复杂环境中的流体稳定性，显著提高了捕获效率。此外，这种CTC检测策略被应用于肝癌患者样本的临床肿瘤治疗评估和进展监测，在将患者分类为完全或部分缓解（CR/PR）方面达到了约83.3%的准确率。总体而言，该策略将有力地推动DNA框架在癌症诊断和疾病进展监测方面的潜在临床应用。
