Programmable Circular Multivalent Nanobody-Targeting Chimeras (mNbTACs) for Multireceptor-Mediated Protein Degradation and Targeted Drug Delivery
Shiqi Jiang
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 China
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
These authors contributed equally to this work
Search for more papers by this authorXinru Lv
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310022 China
These authors contributed equally to this work
Search for more papers by this authorDr. Zhenlin Ouyang
Center for Microbiome Research of Med-X Institute, Department of Critical Care Medicine, Shanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061 China
These authors contributed equally to this work
Search for more papers by this authorHongli Chi
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 China
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorYuchen Zeng
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 China
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorYani Wang
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorJiaxuan He
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorJinling Chen
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 China
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorCorresponding Author
Jingyi Chen
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorKeli An
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorDr. Ming Cheng
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorCorresponding Author
Dr. Yurong Wen
Center for Microbiome Research of Med-X Institute, Department of Critical Care Medicine, Shanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061 China
Search for more papers by this authorCorresponding Author
Dr. Juan Li
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorCorresponding Author
Dr. Penghui Zhang
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorShiqi Jiang
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 China
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
These authors contributed equally to this work
Search for more papers by this authorXinru Lv
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310022 China
These authors contributed equally to this work
Search for more papers by this authorDr. Zhenlin Ouyang
Center for Microbiome Research of Med-X Institute, Department of Critical Care Medicine, Shanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061 China
These authors contributed equally to this work
Search for more papers by this authorHongli Chi
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 China
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorYuchen Zeng
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 China
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorYani Wang
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorJiaxuan He
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorJinling Chen
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 China
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorCorresponding Author
Jingyi Chen
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorKeli An
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorDr. Ming Cheng
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorCorresponding Author
Dr. Yurong Wen
Center for Microbiome Research of Med-X Institute, Department of Critical Care Medicine, Shanxi Provincial Key Laboratory of Sepsis in Critical Care Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061 China
Search for more papers by this authorCorresponding Author
Dr. Juan Li
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorCorresponding Author
Dr. Penghui Zhang
Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022 China
Search for more papers by this authorAbstract
Multispecific therapeutics hold significant promise in drug delivery, protein degradation, and cell recruitment to address clinical issues of tumor heterogeneity, resistance, and immune evasion. However, their modular engineering remains challenging. We developed a targeted degradation platform, termed multivalent nanobody-targeting chimeras (mNbTACs), by encoding diverse nanobody codons on a circular template using DNA printing technology. The homo- or hetero- mNbTACs specifically recognized membrane targets in a multivalent manner and simultaneously recruited scavenger receptors to favor clathrin-/caveolae-dependent endocytosis and lysosomal degradation of multiple proteins with high efficiency and selectivity. We demonstrated that a bispecific doxorubicin-loaded mNbTAC, named Doxo-mvNbsPPH, passively accumulated at tumor sites, specifically interacted with PD−L1 and HER2 targets, and was rapidly transported into lysosome, inducing potent immunogenic cell death and alleviating immune checkpoint evasion. The synergistic boosting of innate and adaptive immunity promoted the infiltration and proliferation of CD8+ T cells in tumor microenvironment (an 11-fold increase) with high toxicity and low exhaustion, eventually enhancing antitumor efficacy. Our mNbTAC platform provides multispecific therapeutics with variable valences and programmed species, whereas it induces targeted protein degradation through multireceptor-mediated endocytosis and lysosomal degradation without the need for lysosome-targeting receptors, representing a general and modular tool to harness extracellular proteome for disease treatment.
Conflict of Interests
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
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