Rational Design of Biocompatible Ir(III) Photosensitizer to Overcome Drug‐Resistant Cancer via Oxidative Autophagy Inhibition

• Published in: Advanced science 2025-01, Vol.12 (2), p.e2407236-n/a
• Main Authors: Park, Mingyu, Nam, Jung Seung, Kim, Taehyun, Yoon, Gwangsu, Kim, Seoyoon, Lee, Chaiheon, Lee, Chae Gyu, Park, Sungjin, Bejoymohandas, Kochan S., Yang, Jihyeon, Kwon, Yoon Hee, Lee, Yoo Jin, Seo, Jeong Kon, Min, Duyoung, Park, Taiho, Kwon, Tae‐Hyuk
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Autophagy - drug effects; Biocompatibility; Cancer therapies; Cell death; Cell Line, Tumor; Chemotherapy; Cytotoxicity; Design; Disease Models, Animal; Drug Design; Drug resistance; Drug Resistance, Neoplasm - drug effects; Endoplasmic reticulum; Humans; Ir(III) complexes; Iridium - chemistry; Iridium - pharmacology; Ligands; Localization; Lysosomes - drug effects; Lysosomes - metabolism; Mice; Microscopy; Molecular weight; Mutation; Neoplasms - drug therapy; Neoplasms - metabolism; Oxidation; Oxidative stress; Oxidative Stress - drug effects; photodynamic therapy; Photosensitizing Agents - pharmacology; protein modifications; Proteins; Reactive Oxygen Species - metabolism; Toxicity
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202407236

Autophagy is a crucial quality control mechanism that degrades damaged cellular components through lysosomal fusion with autophagosomes. However, elevated autophagy levels can promote drug resistance in cancer cells, enhancing their survival. Downregulation of autophagy through oxidative stress is a clinically promising strategy to counteract drug resistance, yet precise control of oxidative stress in autophagic proteins remains challenging. Here, a molecular design strategy of biocompatible neutral Ir(III) photosensitizers is demonstrated, B2 and B4, for precise reactive oxygen species (ROS) control at lysosomes to inhibit autophagy. The underlying molecular mechanisms for the biocompatibility and lysosome selectivity of Ir(III) complexes are explored by comparing B2 with the cationic or the non‐lysosome‐targeting analogs. Also, the biological mechanisms for autophagy inhibition via lysosomal oxidation are explored. Proteome analyses reveal significant oxidation of proteins essential for autophagy, including lysosomal and fusion‐mediator proteins. These findings are verified in vitro, using mass spectrometry, live cell imaging, and a model SNARE complex. The anti‐tumor efficacy of the precise lysosomal oxidation strategy is further validated in vivo with B4, engineered for red light absorbance. This study is expected to inspire the therapeutic use of spatiotemporal ROS control for sophisticated modulation of autophagy. Autophagy inhibition via oxidative stress can overcome drug resistance in cancer, but the dynamic nature of autophagy makes this challenging. Biocompatible Ir(III) photosensitizers are designed to precisely control ROS at lysosomes and inhibit autophagy. Plausible mechanisms are established by proteomic and in vitro evidence. The therapeutic efficacy of the strategy is demonstrated in vivo with the red light‐absorbing photosensitizer, B4.