克服肿瘤细胞凋亡抵抗是增强癌症治疗的主要挑战。细胞焦亡是程序性细胞死亡 (PCD) 的一种裂解形式，涉及炎症小体、Gasdermin 家族蛋白和半胱氨酸蛋白酶，为癌症治疗提供了潜力。虽然光动力疗法 (PDT) 可以通过激活光敏剂 (PS) 产生活性氧 (ROS) 来诱导细胞焦亡，但许多 PS 缺乏特定的亚细胞靶标，并且仅限于第一个近红外窗口，可能会降低治疗效果。因此，开发有效的、深穿透的、针对细胞器的焦亡介导的光疗法对于癌症治疗策略至关重要。在这里，我们合成了四种具有不同苯环数的噻吩鎓结构分子，以初步探索它们的光动力学性质。近红外-II (NIR-II) PS Z1 具有较高的苯环数，表现出优异的 ROS 生成和线粒体靶向能力以及较大的斯托克斯位移。通过纳米沉淀方法，Z1 纳米粒子 (NPs) 在 808 nm 激光照射下也表现出高 ROS 生成（尤其是 I 型 ROS），导致有效的线粒体功能障碍以及联合焦亡和凋亡。此外，它们通过 NIR-II 荧光成像 (NIR-II FI) 和光声成像 (PAI) 表现出卓越的肿瘤靶向能力。此外，Z1 NPs 介导的光疗可有效抑制肿瘤生长，且副作用最小。我们的研究结果为癌症治疗提供了一种有前景的策略，值得在 PDT 中进行进一步的临床前研究。© 2024 Wiley‐VCH GmbH。

Overcoming tumor apoptosis resistance is a major challenge in enhancing cancer therapy. 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-infrared window, potentially reducing treatment effectiveness. Therefore, developing effective, deep-penetrating, organelle-targeted pyroptosis-mediated 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-infrared-II (NIR-II) PS Z1, with a higher benzene ring count, exhibited superior ROS generation and mitochondria-targeting abilities, and a large Stokes shift. Through nano-precipitation method, Z1 nanoparticles (NPs) also demonstrated high ROS generation (especially type-I ROS) upon 808 nm laser irradiation, leading to efficient mitochondria dysfunction and combined pyroptosis and apoptosis. Moreover, they exhibited exceptional tumor-targeting ability via NIR-II fluorescence imaging (NIR-II FI) and photoacoustic imaging (PAI). Furthermore, Z1 NPs-mediated phototherapy effectively inhibited tumor growth with minimal adverse effects. Our findings offer a promising strategy for cancer therapy, warranting further preclinical investigations in PDT.© 2024 Wiley‐VCH GmbH.