Homologous Targeting Cascade Nanobioreactor for Autophagy Inhibition Amplified Tumor Catalytic Therapy

Catalytic therapy based on elaborate nanomedicine is emerging as a pioneering modality for tumor-specific treatment. However, its therapeutic efficiency is usually compromised by the self-protective mechanism of cancer cells, such as autophagy. Herein, a homologous targeting cascade nanobioreactor (denoted as CQ/CuZ@M4T1-G) was developed for the autophagy inhibition amplified enzymic-Fenton like catalytic therapy. CQ/CuZ@M4T1-G was constructed by wearing Cu2+-doped and chloroquine (CQ) loaded zeolitic imidazolate framework with glucose oxidase (GOx) anchored tumor cell membrane. The GOx-driven glycolysis effectively cut off glucose supply for starvation therapy, which also provided abundant H2O2 and decreased pH. Meanwhile, the released Cu2+ was reduced to Cu+ by glutathione and converted the elevated H2O2 into highly toxic middotOH via a Cu+-mediated Fenton-like reaction in the tumor. More importantly, autophagy inhibitor CQ was applied to block downstream autophagic flux and hinder the self-protection pathway. Thus, the tumor succumbed to the severe stress of an enzymatic-Fenton like cascading reaction, yielding a remarkable therapeutic effect as demonstrated by both in vitro and in vivo results. Our study provides a promising regimen mediated by the cascade nanobioreactor for a new type of oncotherapy in the future.