无创且高效的光动力疗法（PDT）有望规避传统骨肉瘤（OS）治疗的耐药性。然而，应用于OS的高功率PDT常常会诱导光热作用，导致正常细胞破裂、持续炎症和不可逆的血管损伤。尽管低功率 PDT 相对安全，但它不会因活性氧 (ROS) 产生不足而引起严重的 DNA 损伤。在此，在低功率PDT中引入了非ROS依赖性DNA损伤敏化策略，以提高OS的治疗效率，其中以低激光功率实现更高的细胞凋亡。受单宁酸 (TA) 出色的 DNA 损伤性能的启发，基于 TA 的金属酚网络 (MPN) 被设计用于封装疏水性光敏剂 (红紫素 18)，以充当 DNA 损伤敏化纳米增效剂 (TCP NP)。特别是，在低功率激光照射下，TCP NPs 可以立即增强 ROS，引发线粒体功能障碍，同时上调 TA 引发的 DNA 损伤水平，增强 PDT 敏化，从而产生有效的抗肿瘤作用。此外，TCP NPs 在肿瘤中表现出长期保留，极大地有利于持续的抗肿瘤性能。总体而言，这项研究为通过增强 DNA 损伤水平来提高低功率 PDT 的敏感性提供了新的思路，并将有益于先进的 OS 治疗。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Non-invasive and efficient photodynamic therapy (PDT) holds great promise to circumvent resistance to traditional osteosarcoma (OS) treatments. Nevertheless, high-power PDT applied in OS often induces photothermogenesis, resulting in normal cells rupture, sustained inflammation and irreversible vascular damage. Despite its relative safety, low-power PDT fails to induce severe DNA damage for insufficient reactive oxygen species (ROS) production. Herein, a non-ROS-dependent DNA damage-sensitizing strategy is introduced in low-power PDT to amplify the therapeutic efficiency of OS, where higher apoptosis is achieved with low laser power. Inspired by the outstanding DNA damage performance of tannic acid (TA), TA-based metal phenolic networks (MPNs) are engineered to encapsulate hydrophobic photosensitizer (purpurin 18) to act as DNA damage-sensitized nanosynergists (TCP NPs). Specially, under low-power laser irradiation, the TCP NPs can boost ROS instantly to trigger mitochondrial dysfunction simultaneously with upregulation of DNA damage levels triggered by TA to reinforce PDT sensitization, evoking potent antitumor effects. In addition, TCP NPs exhibit long-term retention in tumor, greatly benefiting sustained antitumor performances. Overall, this study sheds new light on promoting the sensitivity of low-power PDT by strengthening DNA damage levels and will benefits advanced OS therapy.Copyright © 2024 Elsevier Inc. All rights reserved.