利用癌细胞的内源性特征，DNA纳米机器的响应性激活在肿瘤治疗中取得了巨大成功。与外部光照射等额外刺激相结合提供了DNA纳米机器激活的时空控制。然而，考虑到普通光源的宏观暴露面积，细胞水平的特定激活仍然具有挑战性。位于细胞膜上的DNA逻辑门有助于细胞特异性，但在操作过程中输入DNA链的自由扩散会降低效率，并导致实体瘤周围正常细胞的副作用。
该文中，研究人员设计了一种跨膜DNA逻辑计算策略，仅在复杂实体肿瘤微环境中的癌细胞中激活DNA纳米机器。通过在上转换纳米颗粒上修饰DNA链，制备了DNA纳米机器多壳UCNPs DNA。LA-apt，一种锚定到癌细胞膜过表达受体的DNA链，和细胞内miRNA-21分别作为输入1和2。在细胞膜上与输入1杂交不仅在DNA纳米机器上暴露miRNA-21识别区域，而且还将其传递到癌细胞中。与细胞内输入2的级联杂交完成“和”门操作并释放DNA链L2作为输出。L2作为操作DNA纳米机器的触发器，相应地激活光敏剂Rose Bengal产生活性氧。通过DNA纳米机器在癌细胞膜上的“和”门操作，在复杂的实体瘤微环境中实现了仅对癌细胞的高度精确治疗，可能成为实体瘤精确治疗的一种有希望的方式。
附：英文原文
Title: Activating a DNA Nanomachine via Computation across Cancer Cell Membranes for Precise Therapy of Solid Tumors
Author: Yue Zhang, Weiwei Chen, Yanyun Fang, Xiaobo Zhang, Ying Liu, Huangxian Ju
Issue&Volume: September 13, 2021
Abstract: Taking advantage of cancer cells’ endogenous characters, the responsive activation of DNA nanomachines has achieved great success in tumor therapy. Combining with extra stimuli e osuch as external light irradiation provided spatiotemporal control of DNA nanomachine activation. However, specific activation at the cellular level is still challenging considering the macroscopic-scale exposure area of usual light sources. DNA logic gates located at the cell membrane contributed to cellular specificity, but the free diffusion of input DNA strands during the operation process would impair efficiency and result in side effects to circumjacent normal cells in solid tumors. Here we design a transmembrane DNA logical computation strategy to activate a DNA nanomachine only in cancer cells from a complex solid tumor microenvironment. The DNA nanomachine multishell UCNPs-DNA is prepared by modifying DNA strands on upconversion nanoparticles. LA-apt, a DNA strand anchoring to a cancer cell membrane overexpressed receptor, and intracellular miRNA-21 served as inputs 1 and 2, respectively. Hybridization with input 1 at the cell membrane not only exposes the miRNA-21 recognition region at the DNA nanomachine, but also delivers it into cancer cells. The cascade hybridization with intracellular input 2 completes the “AND” gate operation and releases a DNA strand L2 as output. L2 acts as the trigger to operate the DNA nanomachine and correspondingly activates the photosensitizer Rose Bengal for reactive oxygen species generation. Through the “AND” gatperation of the DNA nanomachine across the cancer cell membrane, highly precise therapy only to cancer cells is achieved in a complex solid tumor microenvironment, which could become a promising modality for precise therapy of solid tumors.
DOI: 10.1021/jacs.1c06361
Source: https://pubs.acs.org/doi/10.1021/jacs.1c06361
