Programmable Bacterial Architects Crafting Sonosensitizers for Tumor‐Specific Sonodynamic Immunotherapy
Abstract
AbstractSonodynamic therapy (SDT) is a non‐invasive cancer treatment that uses ultrasound to activate sonosensitizers for selective tumor ablation. With its superior tissue penetration compared to photodynamic therapy, SDT demonstrates the potential to stimulate antitumor immune responses by modulating the tumor microenvironment. However, its clinical application remains limited by poor tumor specificity and suboptimal sonosensitizer accumulation, which reduces efficacy and causes off‐target effects. To address these challenges, an Engineered Probiotic‐based Calibrated 5‐ALA Supply system (SPEC5) is developed to confer tumor selectivity for SDT. Engineered non‐pathogenic E. coli with recombinant plasmids enables efficient 5‐ALA biosynthesis through kinetic remodeling. Homologous tumor cell membrane cloaking further enhances tumor targeting and immune evasion. Upon intravenous injection, SPEC5 selectively colonizes in the tumor, supporting the sonosensitizer protoporphyrin IX (PpIX) in situ biosynthesis via 5‐aminolevulinic acid (5‐ALA) continuous supply. A hypoxia‐inducible promoter regulating O‐acetylserine sulfhydrylase ensures the tumor specificity of PpIX production. This system achieves robust sensitizer accumulation in tumors, enhancing SDT efficacy and inducing potent antitumor immune activation with minimal systemic toxicity. Post‐treatment, the bacteria are rapidly cleared to ensure safety. This study presents a novel strategy for tumor‐specific sonosensitizer supply, revolutionizing 5‐ALA‐based SDT and paving the way for advanced tumor‐targeted therapies with enhanced immunotherapeutic outcomes.
Article Details
Authors (9)
Zuo Yang
Department of Laboratory Medicine Zhongnan Hospital of Wuhan University Engineering Research Center of Organosilicon Compounds & Materials (Ministry of Education) Hubei Key Lab on Organic and Polymeric OptoElectronic Materials College of Chemistry and Molecular Sciences The Institute for Advanced Studies and TaiKang Center for Life and Medical Sciences Wuhan University Wuhan 430072 China
Zhiping Jiao
Lab of Molecular Imaging and Translational Medicine (MITM) Engineering Research Center of Molecular & Neuroimaging Ministry of Education School of Life Science and Technology Xidian University Xi'an Shaanxi 710126 P. R. China
Zhuang Chen
Lab of Molecular Imaging and Translational Medicine (MITM), Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University & International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment, 266 Xinglong Section of Xifeng Road, Xi’an, Shaanxi 710126, P. R. China
Chaoqiang Qiao
Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology
Chuting Huang
School of Physics & Electronics, Henan University 1 , Kaifeng 475004,
Lingyun Wang
Zhiping Rao
Lab of Molecular Imaging and Translational Medicine (MITM) Engineering Research Center of Molecular & Neuroimaging Ministry of Education School of Life Science and Technology Xidian University Xi'an Shaanxi 710126 P. R. China
Ruili Zhang
Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology
Zhongliang Wang
Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology