Li Jie, Mao Xiuhai, Zhao Tiantian, Fang Weina, Jin Yangyang, Liu Mengmeng, Fan Chunhai, Tian Yang
School of Chemistry and Molecular Engineering, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University, Shanghai, 200241, China.
Shanghai Key Laboratory for Nucleic Acids Chemistry and Nanomedicine, Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
Angew Chem Int Ed Engl. 2025 Jan 27;64(5):e202416988. doi: 10.1002/anie.202416988. Epub 2024 Nov 19.
Spherical nucleic acids (SNAs) hold substantial therapeutic potential for the delivery of small interfering RNAs (siRNAs). Nevertheless, their potential remains largely untapped due to the challenges of cytosolic delivery. Inspired by the dynamic, spiky architecture of coronavirus, an interface engineering approach based on a tetrahedral DNA framework (tDF) is demonstrated for the development of coronavirus-mimicking SNAs. By exploiting their robustness and precise construction, tDFs are evenly arranged on the surface of core nanoparticles (NPs) with flexible conformations, generating a dynamic, spiky architecture. This spiky architecture in tetrahedral DNA framework-based SNAs (tDF-SNAs) substantially improve siRNAs duplex efficiency from 20 % to 95 %. Meanwhile, tDF-SNAs changed the endocytosis pathway to clathrin-independent cellular engulfment pathway and enhanced the cellular uptake efficiency. Due to these advances, the delivery efficiency of siRNA molecules by tDF-SNAs is 1-2 orders of magnitude higher than that of SNAs, resulting in a 2-fold increase in gene silencing efficacy. These results show promise in the development of bioinspired siRNAs delivery systems for intracellular applications.
球形核酸（SNA）在小干扰RNA（siRNA）递送方面具有巨大的治疗潜力。然而，由于胞质递送的挑战，它们的潜力在很大程度上尚未得到开发。受冠状病毒动态、带刺结构的启发，展示了一种基于四面体DNA框架（tDF）的界面工程方法，用于开发模仿冠状病毒的SNA。通过利用其稳健性和精确构建，tDF以灵活的构象均匀排列在核心纳米颗粒（NP）表面，产生动态、带刺的结构。基于四面体DNA框架的SNA（tDF-SNA）中的这种带刺结构将siRNAs双链体效率从20%大幅提高到95%。同时，tDF-SNA将内吞途径转变为不依赖网格蛋白的细胞吞噬途径，并提高了细胞摄取效率。由于这些进展，tDF-SNA对siRNA分子的递送效率比SNA高1-2个数量级，导致基因沉默效果提高了2倍。这些结果为开发用于细胞内应用的仿生siRNA递送系统带来了希望。
