State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
Department of Radiology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
J Am Chem Soc. 2022 Dec 21;144(50):23061-23072. doi: 10.1021/jacs.2c10409. Epub 2022 Dec 11.
RNA interference (RNAi) has proved to be a promising modality for disease treatment. However, the promise of conventional RNA therapeutics for clinical application is severely impeded by low delivery efficiency and susceptibility of RNAs to serum RNases. Therefore, developing advanced RNAi technology is an increasing demand for achieving precise medicine. Herein, for the first time, we propose an alkaline phosphatase (ALP)-controllable and red light-activated RNA modification (ALARM) approach for anti-tumor therapeutic application. An ALP-responsive NIR fluorogenic probe -RCP consisting of a tumor-targeting cyclic RGD peptide, an ALP-activated photosensitizer CyOP, and an O-susceptible furan module for RNA modification was rationally designed and synthesized. Studies have demonstrated that -RCP can specifically target to liver carcinoma HepG2 cells and spontaneously emit activated NIR/photoacoustic signals upon cleavage by the ALP enzyme, allowing for sensitive detection of ALP-positive tumors. More notably, we surprisingly found that the capability of -RCP producing singlet oxygen (O) under red light irradiation could be simultaneously unlocked, which can ignite the covalent cyclization reaction between furan and nucleobases of intracellular RNA molecules, leading to significant mitochondrial damage and severe apoptosis of tumor cells, in consequence realizing efficient tumor suppression. Most importantly, the potential therapeutic mechanism was first explored on the transcriptomic level. This delicate ALARM strategy may open up new insights into cancer gene therapy.
RNA 干扰 (RNAi) 已被证明是一种很有前途的疾病治疗方法。然而，传统 RNA 疗法在临床应用中的应用前景受到递送效率低和 RNA 对血清 RNase 易感性的严重阻碍。因此，开发先进的 RNAi 技术是实现精准医学的迫切需求。在此，我们首次提出了一种碱性磷酸酶 (ALP) 可控和红光激活的 RNA 修饰 (ALARM) 方法，用于抗肿瘤治疗应用。一种由肿瘤靶向环状 RGD 肽、ALP 激活的光敏剂 CyOP 和用于 RNA 修饰的 O 敏感呋喃模块组成的 ALP 响应近红外荧光探针 -RCP 被合理设计和合成。研究表明，-RCP 可以特异性靶向肝癌 HepG2 细胞，并在 ALP 酶切割时自发发出激活的近红外/光声信号，从而能够灵敏地检测 ALP 阳性肿瘤。更值得注意的是，我们惊讶地发现，-RCP 在红光照射下产生单线态氧 (O) 的能力可以同时被解锁，这可以引发呋喃和细胞内 RNA 分子碱基之间的共价环化反应，导致线粒体严重损伤和肿瘤细胞严重凋亡，从而实现有效的肿瘤抑制。最重要的是，我们首次在转录组水平上探索了潜在的治疗机制。这种精细的 ALARM 策略可能为癌症基因治疗开辟新的思路。
