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

IF 13.9 Q1 CHEMISTRY, MULTIDISCIPLINARY Aggregate (Hoboken, N.J.) Pub Date : 2024-04-29 DOI:10.1002/agt2.568
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
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Abstract

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 Mal-thiol 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.

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超声激活原位点击化学触发自噬体追踪,增强自噬阻断和癌症协同治疗效果
研究表明,阻断细胞保护性自噬可有效提高声动力疗法(SDT)的疗效。然而,自噬体对抗自噬药物的认识有限,阻碍了自噬抑制的临床应用。为了将自噬抑制剂羟氯喹(HCQ)有效地递送至自噬体,我们利用了一种基于巯基(-SH)和马来酰亚胺(Mal)基团间原位点击化学的策略,以触发自噬体追踪并协同抑制肿瘤生长。通过将马来酰亚胺修饰的HCQ(MHCQ)封装到具有声敏化剂特性的锰卟啉基金属有机框架中,然后在其上包覆聚乙二醇脂质体膜,合成了级联纳米反应器。超声波照射后,SDT 诱导的凋亡细胞释放出带有游离 -SH 基团的受损蛋白质,MHCQ 通过 Mal-thiol 点击反应迅速在原位捕获这些蛋白质。当自噬体主动包裹受损蛋白质进行解毒时,它们会同时内化锚定在蛋白质上的 HCQ。在这种情况下,抗自噬药物可以主动追踪细胞内的自噬体,而不是在细胞质中被动扩散。HCQ 与自噬囊泡之间的相互作用大大增强,从而提高了自噬的阻断效率,导致细胞完全死亡。总之,这项采用智能设计的研究为改善细胞内自噬体的靶向递送提供了一种前景广阔的策略,从而提高了抗肿瘤治疗的效果。
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17.40
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审稿时长
7 weeks
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