Ultrasound-activated in situ click chemistry to trigger autophagosome tracking for enhanced autophagy blockade and synergistic cancer therapy  

作　　者：Weixi Jiang Jingxue Wang Li Chen Xiaoling Qiu Chier Du Hongjin An Xun Guo Xiaoting Wang Junrui Wang Pan Li Zhigang Wang Haitao Ran Zhiyi Zhou Xiaoyuan Chen Jingjing Zhang Jianli Ren 

机构地区：[1]Department of Ultrasound and Chongqing Key Laboratory of Ultrasound Molecular Imaging,the Second Affiliated Hospital of Chongqing Medical University,Chongqing,P.R.China [2]Department of Intensive Care Unit,the Second Affiliated Hospital of Chongqing Medical University,Chongqing,P.R.China [3]Department of Radiology,the Second Affiliated Hospital of Chongqing Medical University,Chongqing,P.R.China [4]Department of General Practice,Chongqing General Hospital,Chongqing,P.R.China [5]Department of Diagnostic Radiology,Yong Loo Lin School of Medicine,National University of Singapore,Singapore,Singapore [6]Nanomedicine Translational Research Program,NUS Center for Nanomedicine,Yong Loo Lin School of Medicine,National University of Singapore,Singapore,Singapore

出　　处：《Aggregate》2024年第4期386-398,共13页聚集体（英文）

基　　金：China Postdoctoral Science Foundation,Grant/Award Numbers:2022TQ0396,2023MD744153;National Natural Science Foundation of China,Grant/Award Numbers:82302218,82171946;CQMU Program for Youth Innovation in Future Medicine,Grant/Award Number:W0026;Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University,Grant/Award Number:KR2023Y044;Chongqing Science and Health Joint Medical Research Project-Young and Middle-Aged High-Level Talent Project,Grant/Award Number:2020GDRC011。

摘　　要：The blockade of cytoprotective autophagy has been demonstrated to effectively enhance the efficacy of sonodynamic therapy(SDT).However,the limited recognition of antiautophagy agents for autophagosomes impedes the clinical application of autophagy inhibition.To efficiently deliver hydroxychloroquine(HCQ),an autophagy inhibitor,to autophagosomes,we utilized a strategy based on in situ click chemistry between sulfhydryl(-SH)and maleimide(Mal)groups to trigger autophagosomes tracking and suppress tumor growth synergistically.A cascade nanoreactor was synthesized by encapsulating Mal-modified HCQ(MHCQ)into a manganese porphyrin-based metal-organic framework with sonosensitizer properties,followed by poly(ethylene glycol)ylated liposomal membrane coating.After ultrasound irradiation,SDT-induced apoptotic cells released damaged proteins with free-SH groups,which MHCQ rapidly captured in situ via a Malthiol click reaction.When autophagosomes actively wrapped damaged proteins for detoxification,they simultaneously internalized HCQ anchored on proteins.In this scenario,antiautophagy drugs could actively track intracellular autophagosomes instead of undergoing passive diffusion in the cytosol.The interaction between HCQ and autophagic vesicles was greatly enhanced,which strengthened the blocking efficiency of autophagy and resulted in complete cell death.Overall,this study with smart design provides a promising strategy for improving intracellular targeted delivery to autophagosomes,thereby enhancing antitumor therapy.

关 键 词：autophagosomes tracking autophagy blockade click reaction sonodynamic therapy synergy 

分 类 号：R730.5[医药卫生—肿瘤]