Efficient microRNAs (miRNA) delivery into cells is a promising strategy for disease therapy, but is a major challenge because the available conventional nonviral vectors have significant drawbacks. In particular, after these vectors are entrapped in lysosomes, the escape efficiency of genes from lysosomes into the cytosol is less than 2%. Here, a novel approach for lethal‐7a (let‐7a) replacement therapy using rod‐shaped active pure drug nanoparticles (≈130 nm in length, PNPs) with a dramatically high drug‐loading of ≈300% as vectors is reported. Importantly, unlike other vectors, the developed PNPs/let‐7a complexes (≈178 nm, CNPs) can enter cells and bypass the lysosomal route to localize to the cytosol, achieving efficient intracellular delivery of let‐7a and a 50% reduction in expression of the target protein (KRAS). Also, CNPs prolong the t_1/2 of blood circulation by ≈threefold and increase tumor accumulation by ≈1.5–2‐fold, resulting in significantly improved antitumor efficacies. Additionally, no damage to normal organs is observed following systemic injection of CNPs. In conclusion, rod‐shaped active PNPs enable efficient and safe delivery of miRNA with synergistic treatment for disease. This nanoplatform would also offer a viable strategy for the potent delivery of proteins and peptides in vitro and in vivo.

中文翻译：

---

棒状活性药物颗粒实现高效、安全的基因传递

有效地将 microRNA (miRNA) 递送到细胞中是一种很有前景的疾病治疗策略，但也是一个重大挑战，因为可用的传统非病毒载体具有显着的缺点。特别是，这些载体被溶酶体捕获后，基因从溶酶体逃逸到细胞质中的效率低于2%。在此，报道了一种使用棒状活性纯药物纳米粒子（长度约 130 nm，PNP）作为载体进行致命 7a（let-7a）替代疗法的新方法，其载药量极高，约为 300%。重要的是，与其他载体不同，所开发的 PNPs/let-7a 复合物（约 178 nm，CNPs）可以进入细胞并绕过溶酶体途径定位于细胞质，实现 let-7a 的高效细胞内递送并将表达量减少 50%目标蛋白（KRAS）的。此外，CNP 可使血液循环的t _1/2延长约三倍，并使肿瘤积累增加约 1.5-2 倍，从而显着提高抗肿瘤功效。此外，全身注射 CNP 后未观察到对正常器官的损害。总之，杆状活性 PNP 能够高效、安全地递送 miRNA，并协同治疗疾病。该纳米平台还将为体外和体内有效输送蛋白质和肽提供可行的策略。