State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
Key Laboratory of Oral Biomedical Research of Zhejiang Province, The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
Adv Mater. 2022 Nov;34(46):e2204287. doi: 10.1002/adma.202204287. Epub 2022 Jul 28.
MicroRNA (miR)-based therapy shows strong potential; however, structural limitations pose a challenge in fully exploiting its biomedical functionality. Tetrahedral framework DNA (tFNA) has proven to be an ideal vehicle for miR therapy. Inspired by the ancient Chinese myth "Sun and Immortal Birds," a novel bioswitchable miR inhibitor delivery system (BiRDS) is designed with three miR inhibitors (the three immortal birds) and a nucleic acid core (the central sun). The BiRDS fuses miR inhibitors within the framework, maximizing their loading capacity, while allowing the system to retain the characteristics of small-sized tFNA and avoiding uncertainty associated with RNA exposure in traditional loading protocols. The RNase H-responsive sequence at the tail of each "immortal bird" enables the BiRDS to transform from a 3D to a 2D structure upon entering cells, promoting the delivery of miR inhibitors. To confirm the application potential, the BiRDS is used to deliver the miR-31 inhibitor, with antiaging effects on hair follicle stem cells, into a skin aging model. Superior skin penetration ability and RNA delivery are observed with significant anti-aging effects. These findings demonstrate the capability and editability of the BiRDS to improve the stability and delivery efficacy of miRs for future innovations.
基于 microRNA（miRNA）的治疗方法具有很大的潜力；然而，结构上的限制对充分发挥其生物医学功能构成了挑战。四面体框架 DNA（tFNA）已被证明是 miRNA 治疗的理想载体。受中国古代神话“日与神鸟”的启发，设计了一种新型的生物可切换 miRNA 抑制剂递药系统（BiRDS），其中包含三个 miRNA 抑制剂（三神鸟）和一个核酸核心（中央太阳）。BiRDS 将 miRNA 抑制剂融合在框架内，最大限度地提高其载药能力，同时使系统保留小尺寸 tFNA 的特性，并避免传统载药方案中与 RNA 暴露相关的不确定性。每个“神鸟”尾部的 RNase H 反应序列使 BiRDS 在进入细胞时能够从 3D 结构转变为 2D 结构，从而促进 miRNA 抑制剂的递药。为了验证应用潜力，将具有抗衰老作用的毛囊干细胞 miR-31 抑制剂递药系统用于皮肤衰老模型。观察到具有优异的皮肤穿透能力和 RNA 递药效果，具有显著的抗衰老作用。这些发现证明了 BiRDS 提高 miRNA 稳定性和递药效果的能力和可编辑性，为未来的创新提供了可能。
