Yin Haohao, Sun Liping, Pu Yinying, Yu Jifeng, Feng Wei, Dong Caihong, Zhou Bangguo, Du Dou, Zhang Yan, Chen Yu, Xu Huixiong
Center of Minimally Invasive Treatment for Tumor, Department of Medical Ultrasound, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, P. R. China.
Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, School of Medicine, Tongji University, Shanghai 200072, P. R. China.
ACS Cent Sci. 2021 Dec 22;7(12):2049-2062. doi: 10.1021/acscentsci.1c01143. Epub 2021 Dec 8.
Sonodynamic therapy (SDT), relying on the generation of reactive oxygen species (ROS), is a promising clinical therapeutic modality for the treatment of hepatocellular carcinoma (HCC) due to its noninvasiveness and high tissue-penetration depth, whereas the oxidative stress and antioxidative defense system in cancer cells significantly restrict the prevalence of SDT. Herein, we initially identified that was immediately activated during SDT, which further inhibited SDT efficacy. To address this intractable issue, an ultrasound remote control of the cluster regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) release system (HMME@Lip-Cas9) was meticulously designed and constructed, which precisely knocks down to alleviate the adverse effects and augment the therapeutic efficiency of SDT. The hematoporphyrin monomethyl ether (HMME) in this system yielded abundant ROS to damage cancer cells under ultrasound irradiation, and meanwhile the generated ROS could induce lysosomal rupture to release Cas9/single guide RNA ribonucleoprotein (RNP) and destroy the oxidative stress-defensing system, significantly promoting tumor cell apoptosis. This study provides a new paradigm for HCC management and lays the foundation for the widespread application of CRISPR/Cas9 with promising clinical translation, meanwhile developing a synergistic therapeutic modality in the combination of SDT with gene editing.
声动力疗法（SDT）依赖于活性氧（ROS）的产生，由于其非侵入性和高组织穿透深度，是一种很有前景的治疗肝细胞癌（HCC）的临床治疗方式，然而癌细胞中的氧化应激和抗氧化防御系统显著限制了SDT的应用。在此，我们首次发现 在SDT过程中被立即激活，这进一步抑制了SDT的疗效。为了解决这个棘手的问题，我们精心设计并构建了一种超声远程控制的成簇规律间隔短回文重复序列（CRISPR）/CRISPR相关蛋白9（Cas9）释放系统（HMME@Lip-Cas9），该系统精确敲低 以减轻不良反应并提高SDT的治疗效率。该系统中的血卟啉单甲醚（HMME）在超声照射下产生大量ROS来损伤癌细胞，同时产生的ROS可诱导溶酶体破裂以释放Cas9/单向导RNA核糖核蛋白（RNP）并破坏氧化应激防御系统，显著促进肿瘤细胞凋亡。本研究为HCC的治疗提供了一种新的模式，为具有前景的临床转化的CRISPR/Cas9的广泛应用奠定了基础，同时开发了一种SDT与基因编辑相结合的协同治疗方式。
