Zhan Rumeng, Zhou Weijie, Ma Hongyu, Zou Menghui, Zhang Mingming, Zhang Weian, Tian Jia
Shanghai Key Laboratory of Functional Materials Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology Shanghai 200237 China
Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences, Peking Union Medical College Tianjin 300192 China
Chem Sci. 2025 Jun 9. doi: 10.1039/d5sc01987g.
Photodynamic therapy (PDT) has emerged as a critical modality in cancer treatment with the merits of non-invasiveness, spatiotemporal control, and minimal drug resistance. However, the clinical application of PDT is often hindered by inherent limitations, including side effects caused by the "always on" state of reactive oxygen species (ROS) and low ROS generation efficiency in hypoxic tumors. To overcome these limitations, we developed a tumor microenvironment (TME) "dual lock-and-key" triggered and endoplasmic reticulum (ER) targeting nanophotosensitizer for fluorescence imaging-guided activatable Type-I PDT and photothermal therapy (PTT). This "smart" nanophotosensitizer remains in an "off" state during systemic circulation, and is specifically activated only in the acidic and GSH-overexpressed TME ("on" state), where its fluorescence, ROS generation, and photothermal conversion capabilities are restored, leading to precise and enhanced phototherapies at tumor sites while minimizing side effects. Sulfur-substituted and ER-targeting hemicyanine induces a large red-shift in absorption, simultaneously generating Type-I ROS and producing a photothermal effect in the ER, thereby enhancing protein deactivation and ER stress. Comprehensive and investigations demonstrated that the TME dual triggered activatable nanophotosensitizer, upon NIR laser irradiation, effectively kills tumor cells, and significantly suppresses tumor growth through fluorescence imaging-guided Type-I PDT and PTT. This work provides a pathway for developing TME-triggered precise phototherapeutics with improved biosafety and potential for clinical translation.
光动力疗法（PDT）已成为癌症治疗中的一种关键方式，具有非侵入性、时空可控性和最小耐药性等优点。然而，PDT的临床应用常常受到其固有局限性的阻碍，这些局限性包括活性氧（ROS）“始终开启”状态所导致的副作用以及缺氧肿瘤中ROS生成效率低下。为了克服这些局限性，我们开发了一种肿瘤微环境（TME）“双锁钥”触发且靶向内质网（ER）的纳米光敏剂，用于荧光成像引导的可激活I型PDT和光热疗法（PTT）。这种“智能”纳米光敏剂在全身循环过程中处于“关闭”状态，仅在酸性且谷胱甘肽（GSH）过表达的TME（“开启”状态）中被特异性激活，在该状态下其荧光、ROS生成和光热转换能力得以恢复，从而在肿瘤部位实现精确且增强的光热疗法，同时将副作用降至最低。硫取代且靶向ER的半菁在吸收光谱上诱导大的红移，同时产生I型ROS并在内质网中产生光热效应，从而增强蛋白质失活和内质网应激。全面的研究表明，这种TME双触发可激活纳米光敏剂在近红外激光照射下，通过荧光成像引导的I型PDT和PTT有效杀死肿瘤细胞，并显著抑制肿瘤生长。这项工作为开发具有更高生物安全性和临床转化潜力的TME触发精确光疗方法提供了一条途径。
