Liu Zhendong, Liu Sainan, Liu Bin, Meng Qi, Yuan Meng, Ma Xinyu, Wang Jiwei, Wang Meifang, Li Kai, Ma Ping'an, Lin Jun
State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China.
School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China.
Angew Chem Int Ed Engl. 2025 Jan 10;64(2):e202414879. doi: 10.1002/anie.202414879. Epub 2024 Nov 6.
Mild photothermal therapy (MPTT) has emerged as a promising therapeutic modality for attenuating thermal damage to the normal tissues surrounding tumors, while the heat-induced upregulation of heat shock proteins (HSPs) greatly compromises the curative efficacy of MPTT by increasing cellular thermo-tolerance. Ferroptosis has been identified to suppress the overexpression of HSPs by the accumulation of lipid peroxides and reactive oxygen species (ROS), but is greatly restricted by overexpressed glutathione (GSH) in tumor microenvironment and undesirable ROS generation efficiency. Herein, a synergistic strategy based on the mutual enhancement of MPTT and ferroptosis is proposed for cleaving HSPs to recover tumor cell sensitivity. A facile method for fabricating a series of Fe-based metal-quinone networks (MQNs) by coordinated assembly is proposed and the representative FTP MQNs possess high photothermal conversion efficiency (69.3 %). Upon 808 nm laser irradiation, FTP MQNs not only trigger effective MPTT to induce apoptosis but more significantly, potentiate Fenton reaction and marked GSH consumption to boost ferroptosis, and the reinforced ferroptosis effect in turn can alleviate the thermal resistance by declining the HSP70 defense and reducing ATP levels. This study provides a valuable rationale for constructing a large library of MQNs for achieving mutual enhancement of MPTT and ferroptosis.
温和光热疗法（MPTT）已成为一种有前景的治疗方式，可减轻对肿瘤周围正常组织的热损伤，然而热诱导的热休克蛋白（HSPs）上调通过增加细胞耐热性极大地损害了MPTT的疗效。铁死亡已被证实可通过脂质过氧化物和活性氧（ROS）的积累来抑制HSPs的过度表达，但在肿瘤微环境中过表达的谷胱甘肽（GSH）和不理想的ROS生成效率极大地限制了铁死亡。在此，提出了一种基于MPTT和铁死亡相互增强的协同策略，用于裂解HSPs以恢复肿瘤细胞敏感性。提出了一种通过配位组装制备一系列铁基金属醌网络（MQNs）的简便方法，代表性的FTP MQNs具有高光热转换效率（69.3%）。在808 nm激光照射下，FTP MQNs不仅引发有效的MPTT以诱导凋亡，更显著的是，增强芬顿反应并显著消耗GSH以促进铁死亡，而增强的铁死亡效应反过来又可通过降低HSP70防御和减少ATP水平来减轻热抗性。本研究为构建大量MQNs文库以实现MPTT和铁死亡的相互增强提供了有价值的理论依据。
