Dual-Targeting Multivalent Aptamer-Drug Hybrids for Synergistic Cancer Immunotherapy

作者：Hongli Chi, Yanlin Du, Wei Lv, Keli An, Xinru Lv, Sining Zhao, Yuxin Zeng, Xinni Liu, Pengju Li, Wangbo Qu, Chunyan Fan, Zheng Wang, Anna S. Kichkailo, Tao Fu, Ming Cheng, Penghui Zhang, Weihong Tan · 发表于：Journal of the American Chemical Society · 年份：2026 · DOI：10.1021/jacs.5c21968 · 被引用次数：1 · 研究领域：interferon and immune responses、Protein Degradation and Inhibitors、Advanced biosensing and bioanalysis techniques

Targeted drug conjugates (TDCs) have transformed cancer therapy by enabling selective delivery of cytotoxic agents, yet most existing designs rely on single-antigen targeting and single-payload architectures that limit efficacy in heterogeneous tumors and restrict opportunities for integrating orthogonal mechanisms of action. Here, we report circular, dual-targeting multivalent aptamer-drug hybrids ( Dual o-mvApDHs D/S ) that codeliver doxorubicin (Dox) and STING agonist (diABZI) for synergistic chemo-immunotherapy. Built on a programmable DNA scaffold with defined valence and high loading capacity, the Dual o-mvApDHs D/S simultaneously engage c-Met and CD71 to enhance tumor-specific uptake through heteromultireceptor-mediated endocytosis, achieving efficient intracellular delivery and robust tumor accumulation in vivo . Within tumor cells, Dox induces genotoxic stress and potent immunogenic cell death, while diABZI activates cGAS-STING signaling to amplify type I interferon responses. This coordinated action remodels the immunosuppressive tumor microenvironment, promoting dendritic cell recruitment and activation, expanding IFN-responsive macrophages and conventional dendritic cells, and driving the proliferation and functional maintenance of cytotoxic CD8 + T cells. Single-cell RNA and TCR sequencing revealed increased TCR diversity, reduced terminal exhaustion, and strengthened effector differentiation in response to combination therapy. Notably, Dual o-mvApDHs D/S synergi...