Intelligent Modular DNA Lysosome-Targeting Chimera Nanodevice for Precision Tumor TherapyClick to copy article linkArticle link copied!
- Meirong CuiMeirong CuiState Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, ChinaMore by Meirong Cui
- Dan ZhangDan ZhangState Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, ChinaMore by Dan Zhang
- Xian ZhengXian ZhengState Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, ChinaMore by Xian Zheng
- Huan ZhaiHuan ZhaiState Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, ChinaMore by Huan Zhai
- Mo XieMo XieState Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, ChinaMore by Mo Xie
- Qin FanQin FanState Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, ChinaMore by Qin Fan
- Lianhui WangLianhui WangState Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, ChinaMore by Lianhui Wang
- Chunhai FanChunhai FanSchool of Chemistry and Chemical Engineering, New Cornerstone Science Laboratory, Frontiers Science Center for Transformative Molecules, Zhangjiang Institute for Advanced Study and National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, ChinaInstitute of Molecular Medicine, Shanghai Key Laboratory for Nucleic Acids Chemistry and Nanomedicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, ChinaMore by Chunhai Fan
- Jie Chao*Jie Chao*E-mail: [email protected]State Key Laboratory of Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, ChinaMore by Jie Chao
Abstract
Lysosome targeting chimeras (LYTACs) have emerged as a powerful modality that can eliminate traditionally undruggable extracellular tumor-related pathogenic proteins, but their low bioavailability and nonspecific distribution significantly restrict their efficacy in precision tumor therapy. Developing a LYTAC system that can selectively target tumor tissues and enable a modular design is crucial but challenging. We here report a programmable nanoplatform for tumor-specific degradation of multipathogenic proteins using an intelligent modular DNA LYTAC (IMTAC) nanodevice. We employ circular DNA origami to integrate predesigned modular multitarget protein binding sites and pH-responsive protein degradation promoters that specifically recognize cell-surface lysosome-shuttling receptors in tumor tissues. By precisely manipulating the stoichiometry and modularity of promoters and ligands targeting diverse proteins, the IMTAC nanodevice enables accurate localization and delivery into tumor tissues, where the acidic tumor microenvironment triggers degradation switch activation, multivalent binding, and efficient degradation of various prespecified proteins. The tissue-specificity and multiple ligands in IMTACs significantly improve the drug utilization rate while reducing off-target effects. Importantly, this system demonstrates the capability of collabo-rative degradation of EGFR and PDL1 in tumor tissue for combined targeting and immunity therapy of hepatocellular carcinoma (HCC), resulting in obvious tumor necrosis and inhibition of tumor growth in vivo even at low concentrations. This study presents a unique strategy for building a general, intelligent, modular, and simple encoded nanoplatform for designing precision medicine degraders and developing proprietary antitumor drugs.
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