虽然基于金属环化合物的光敏剂在生物医学上引起了越来越多的关注，但由于其固有的黑暗毒性和不令人满意的光治疗效率，其临床应用受到了阻碍。因此，我们利用 Ru(ii) 受体的 π-扩张策略，开发出一系列 Ru1-Ru4 的金属环化合物，同时降低了其黑暗毒性并增强了光毒性，从而获得了较高的光毒指数（PI）。这些金属环化合物能够实现深层组织（∼7 mm）荧光成像和活性氧（ROS）产生，并表现出显著的抗肿瘤活性，即使在低氧条件下仍然如此。值得注意的是，Ru4 具有最低的黑暗毒性、最高的 ROS 产生能力和最佳的 PI（∼146）。理论计算证实，Ru4 表现出最大的立体堆积和最低的单重三重能量差（ΔE ST，0.62 eV）。体内研究证实，Ru4 允许针对 A549 肿瘤进行有效和安全的光治疗。这项工作有望为高性能金属基光敏剂的设计开辟新道路，以便进行潜在的临床应用。

Although metallacycle-based photosensitizers have attracted increasing attention in biomedicine, their clinical application has been hindered by their inherent dark toxicity and unsatisfactory phototherapeutic efficiency. Herein, we employ a π-expansion strategy for ruthenium acceptors to develop a series of Ru(ii) metallacycles (Ru1-Ru4), while simultaneously reducing dark toxicity and enhancing phototoxicity, thus obtaining a high phototoxicity index (PI). These metallacycles enable deep-tissue (∼7 mm) fluorescence imaging and reactive oxygen species (ROS) production and exhibit remarkable anti-tumor activity even under hypoxic conditions. Notably, Ru4 has the lowest dark toxicity, highest ROS generation ability and an optimal PI (∼146). Theoretical calculations verify that Ru4 exhibits the largest steric bulk and the lowest singlet-triplet energy gap (ΔE ST, 0.62 eV). In vivo studies confirm that Ru4 allows for effective and safe phototherapy against A549 tumors. This work thus is expected to open a new avenue for the design of high-performance metal-based photosensitizers for potential clinical applications.This journal is © The Royal Society of Chemistry.