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

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 ( M HCQ) 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 M HCQ 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.