Affiliation:
1. Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics – Hubei Bioinformatics & Molecular Imaging Key Laboratory Department of Biomedical Engineering College of Life Science and Technology Huazhong University of Science and Technology Wuhan Hubei 430074 P. R. China
2. Key Laboratory of Biomedical Photonics (HUST) Ministry of Education Huazhong University of Science and Technology Wuhan Hubei 430074 P. R. China
3. NMPA Research Base of Regulatory Science for Medical Devices & Institute of Regulatory Science for Medical Devices Huazhong University of Science and Technology Wuhan Hubei 430074 P. R. China
4. Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine Zhejiang Provincial People's Hospital Affiliated People's Hospital Hangzhou Medical College Hangzhou Zhejiang 310014 P. R. China
Abstract
AbstractCustomizable and number‐tunable enzyme delivery nanocarriers will be useful in tumor therapy. Herein, a phage vehicle, T4‐Lox‐DNA‐Fe (TLDF), which adeptly modulates enzyme numbers using phage display technology to remodel the tumor microenvironment (TME) is presented. Regarding the demand for lactic acid in tumors, each phage is engineered to display 720 lactate oxidase (Lox), contributing to the depletion of lactic acid to restructure the tumor's energy metabolism. The phage vehicle incorporated dextran iron (Fe) with Fenton reaction capabilities. H2O2 is generated through the Lox catalytic reaction, amplifying the H2O2 supply for dextran iron‐based chemodynamic therapy (CDT). Drawing inspiration from the erythropoietin (EPO) biosynthetic process, an EPO enhancer is constructed to impart the EPO‐Keap1 plasmid (DNA) with tumor hypoxia‐activated functionality, disrupting the redox homeostasis of the TME. Lox consumes local oxygen, and positive feedback between the Lox and the plasmid promotes the expression of kelch ECH Associated Protein 1 (Keap1). Consequently, the downregulation of the antioxidant transcription factor Nrf2, in synergy with CDT, amplifies the oxidative killing effect, leading to tumor suppression of up to 78%. This study seamlessly integrates adaptable T4 phage vehicles with bio‐intelligent plasmids, presenting a promising approach for tumor therapy.
Funder
National Natural Science Foundation of China
China Postdoctoral Science Foundation