The blockade of cytoprotective autophagy has been demonstrated to effectively enhance the efficacy of sonodynamic therapy(SDT).However,the limited recogni-tion of antiautophagy agents for autophagosomes impedes the cli...The blockade of cytoprotective autophagy has been demonstrated to effectively enhance the efficacy of sonodynamic therapy(SDT).However,the limited recogni-tion 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 proper-ties,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 detoxifi-cation,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 effi-ciency 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.展开更多
基金China Postdoctoral Science Foundation,Grant/Award Numbers:2022TQ0396,2023MD744153National Natural Science Foundation of China,Grant/Award Numbers:82302218,82171946+2 种基金CQMU Program for Youth Innovation in Future Medicine,Grant/Award Number:W0026Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University,Grant/Award Number:KR2023Y044Chongqing Science and Health Joint Medical Research Project-Young and Middle-Aged High-Level Talent Project,Grant/Award Number:2020GDRC011。
文摘The blockade of cytoprotective autophagy has been demonstrated to effectively enhance the efficacy of sonodynamic therapy(SDT).However,the limited recogni-tion 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 proper-ties,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 detoxifi-cation,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 effi-ciency 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.
