Flying‐Saucer‐Shaped Nanoheterojunctions with Enhanced Colorectal Tumor Accumulation for Increased Oxidative Stress and Immunometabolic Regulation

Abstract The treatment outcomes of nanomedicines against colorectal cancer are severely restricted by their insufficient accumulation in the tumor tissues, unsatisfactory antitumor effect, and weak immunometabolic modulation. To address these issues, flying‐saucer‐shaped nanoheterojunctions by coating copper oxide (Cu x O) onto the surface of PEGylated zinc oxide (ZnO) nanoparticles are constructed. When exposed to ultrasound, the resultant Cu x O@ZnO nanoheterojunctions exhibit increased locomotor activities, facilitating colorectal mucus infiltration, deep tumor penetration, and tumor cell internalization. The decoration of Cu x O suppresses the rapid recombination of electrons and holes in Cu x O@ZnO exposed to ultrasound, promoting the production of singlet oxygen and hydroxyl radical, which are generated by Cu x O through a Fenton‐like chemodynamic reaction and Cu x O@ZnO through sonodynamic reaction. After rectal administration, the sono‐chemodynamic Cu x O@ZnO plus PD‐L1 antibodies effectively inhibit the growth of orthotopic and distant tumors. It elicits immunometabolic responses by inducing immunogenic cell death, activating the interferon genes signaling pathway stimulator, and inhibiting glucose transport and the glycolytic signaling pathways. This combined modality also increases the proportion of beneficial microbes ( e.g ., Bifidobacterium ) and decreases the abundance of harmful microorganisms ( e.g ., Romboutsia ) in the intestine. This treatment modality (Cu x O@ZnO plus ultrasound and PD‐L1 antibodies) is a promising strategy for the synergistic treatment of colorectal cancer.