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Abstract：
Gas therapy is emerging as a highly promising therapeutic strategy for cancer treatment. However, there are limitations, including the lack of targeted subcellular organelle accuracy and spatiotemporal release precision, associated with gas therapy. In this study, we developed a series of photoactivatable nitric oxide (NO) donors NRh-R-NO (R = Me, Et, Bn, iPr, and Ph) based on an N-nitrosated upconversion luminescent rhodamine scaffold. Under the irradiation of 808 nm light, only NRh-Ph-NO could effectively release NO and NRh-Ph with a significant turn-on frequency upconversion luminescence (FUCL) signal at 740 nm, ascribed to lower N-N bond dissociation energy. We also investigated the involved multistage near-infrared-controlled cascade release of gas therapy, including the NO released from NRh-Ph-NO along with one NRh-Ph molecule generation, the superoxide anion O2⋅- produced by the photodynamic therapy (PDT) effect of NRh-Ph, and highly toxic peroxynitrite anion (ONOO‒) generated from the co-existence of NO and O2⋅-. After mild nano-modification, the nanogenerator (NRh-Ph-NO NPs) empowered with superior biocompatibility could target mitochondria. Under an 808 nm laser irradiation, NRh-Ph-NO NPs could induce NO/ROS to generate RNS, causing a decrease in the mitochondrial membrane potential and initiating apoptosis by caspase-3 activation, which further induced tumor immunogenic cell death (ICD). In vivo therapeutic results of NRh-Ph-NO NPs showed augmented RNS-potentiated gas therapy, demonstrating excellent biocompatibility and effective tumor inhibition guided by real-time FUCL imaging. Collectively, this versatile strategy defines the targeted RNS-mediated cancer therapy.
摘要：
气体疗法正在成为一种非常有前途的癌症治疗策略。然而,有局限性,包括缺乏靶向亚细胞器的准确性和时空释放的准确性，与气体治疗有关。在这项研究中,我们开发了一系列可光活化的一氧化氮（NO）供体NRh-R-NO（R=Me，Et,Bn,iPr,和Ph）基于N-亚硝化上转换发光罗丹明支架。在808nm光的照射下，只有NRh-Ph-NO可以有效释放NO和NRh-Ph，在740nm处具有显著的开启频率上转换发光(FUCL)信号，归因于较低的N-N键离解能。我们还调查了涉及的多级近红外控制级联释放气体治疗，包括从NRh-Ph-NO释放的NO以及一个NRh-Ph分子的产生，NRh-Ph的光动力治疗(PDT)效应产生的超氧阴离子O2·-，和高毒性的过氧亚硝酸盐阴离子（ONOO-）由NO和O2·-的共存产生。经过温和的纳米改性，具有优异生物相容性的纳米发电机（NRh-Ph-NONPs）可以靶向线粒体。在808nm激光照射下，NRh-Ph-NONPs可诱导NO/ROS产生RNS,导致线粒体膜电位降低，并通过caspase-3激活启动细胞凋亡，这进一步诱导了肿瘤免疫原性细胞死亡(ICD)。NRh-Ph-NONP的体内治疗结果显示增强的RNS增强的气体治疗，通过实时FUCL成像显示出优异的生物相容性和有效的肿瘤抑制作用。总的来说，这一通用策略定义了靶向RNS介导的癌症治疗.
