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Pyroptosis, a lytic form of programmed cell death (PCD) involving inflammasomes, Gasdermin family proteins, and cysteine proteases, offers potential in cancer treatment. While photodynamic therapy (PDT) can induce pyroptosis by generating reactive oxygen species (ROS) through the activation of photosensitizers (PSs), many PSs lack specific subcellular targets and are limited to the first near\u2010infrared window, potentially reducing treatment effectiveness. Therefore, developing effective, deep\u2010penetrating, organelle\u2010targeted pyroptosis\u2010mediated phototherapy is essential for cancer treatment strategies. Here, we synthesized four molecules with varying benzene ring numbers in thiopyrylium structures to preliminarily explore their photodynamic properties. The near\u2010infrared\u2010II (NIR\u2010II) PS Z1, with a higher benzene ring count, exhibited superior ROS generation and mitochondria\u2010targeting abilities, and a large Stokes shift. Through nano\u2010precipitation method, Z1 nanoparticles (NPs) also demonstrated high ROS generation (especially type\u2010I ROS) upon 808\u2005nm laser irradiation, leading to efficient mitochondria dysfunction and combined pyroptosis and apoptosis. Moreover, they exhibited exceptional tumor\u2010targeting ability via NIR\u2010II fluorescence imaging (NIR\u2010II FI) and photoacoustic imaging (PAI). Furthermore, Z1 NPs\u2010mediated phototherapy effectively inhibited tumor growth with minimal adverse effects. Our findings offer a promising strategy for cancer therapy, warranting further preclinical investigations in PDT.<\/jats:p>","DOI":"10.1002\/anie.202408874","type":"journal-article","created":{"date-parts":[[2024,7,7]],"date-time":"2024-07-07T22:34:11Z","timestamp":1720391651000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":101,"title":["A Mitochondria\u2010Targeted Photosensitizer for Combined Pyroptosis and Apoptosis with NIR\u2010II Imaging\/Photoacoustic Imaging\u2010Guided Phototherapy"],"prefix":"10.1002","volume":"63","author":[{"given":"Ben","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Organic Electronics and Information Displays, Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), School of Materials Science and Engineering Nanjing University of Posts and Telecommunications  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