Lab‐in‐Cell: A Covalent Photosensitizer Reverses Hypoxia and Evokes Ferroptosis and Pyroptosis for Enhanced Anti‐Tumor Immunity
Abstract
Abstract Photodynamic immunotherapy presents a non‐invasive strategy characterized by spatiotemporal control and minimal side effects to induce immunogenic cell death (ICD). This approach significantly enhances the release of tumor‐associated antigens and damage‐associated molecular patterns, thereby improving cancer immunotherapy outcomes. However, hypoxia and antioxidant defenses at tumor sites considerably diminish the efficacy of photodynamic immunotherapy. In this work, a covalent warhead, alkyneamide, is introduced into an AIE photosensitizer to develop a novel covalent photosensitizer, MBTP‐PA, which targets redox systems and facilitates ferroptosis‐ and pyroptosis‐mediated photodynamic immunotherapy by thiol‐yne click reactions. The covalent photosensitizer interacts with intracellular thiol compounds such as cysteine and glutathione, disrupting the intracellular antioxidant system and alleviating hypoxia. This results in enhanced photodynamic therapy (PDT) efficacy compared to the non‐covalent photosensitizer MBTP‐A. Furthermore, in conjunction with PDT, this reaction therapy can activate ICD through ferroptosis and pyroptosis, thereby enhancing anti‐tumor immunity. Notably, in vivo injection of MBTP‐PA nanoparticles at the tumor site led to the elimination of primary tumors, inhibiting distal tumors and exhibiting minimal side effects. Therefore, this work not only integrates the thiol‐yne click reactions into cellular systems, significantly enhancing the efficacy of photodynamic immunotherapy but also paves the way for developing novel photosensitizers.
Article Details
Authors (12)
Bingnan Wang
School of Chemistry and Chemical Engineering Hainan University Haikou China
Guiquan Zhang
State Key Laboratory of Luminescent Materials and Devices Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates Center for Aggregation‐Induced Emission AIE Institute South China University of Technology Guangzhou 510640 China
Zhizai Chen
Department of Gynecology Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 China
Hanchen Shen
Innovative Centre for Flexible Devices (iFLEX), Max Planck−NTU Joint Laboratory for Artificial Senses, School of Materials Science and Engineering
Chunyang Li
School of Ecology, Environment and Resources, Guangdong University of Technology, Guangzhou, China.
Jianqing Li
Meixi Yi
State Key Laboratory of Luminescent Materials and Devices Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates Center for Aggregation‐Induced Emission AIE Institute South China University of Technology Guangzhou 510640 China
Jianwei Sun
Ryan T. K. Kwok
Department of Chemistry, the Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Department of Chemical and Biological Engineering, State Key Laboratory of Nervous System Disorders, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR 999077, China
Jacky W. Y. Lam
Department of Chemistry, the Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Department of Chemical and Biological Engineering, State Key Laboratory of Nervous System Disorders, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR 999077, China
Anjun Qin
State Key Laboratory of Luminescent Materials and Devices Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates South China University of Technology Guangzhou China
Ben Zhong Tang
School of Science and Engineering, Guangdong Basic Research Center of Excellence for Aggregate Science, The Chinese University of Hong Kong (Shenzhen), Longgang, Shenzhen 518172, Guangdong, P. R. China