在各种癌症模型中外源递送 miRNA 来模拟和恢复 miRNA-34a 活性，在癌症治疗中具有重大前景。然而，其有效性常常受到挑战的阻碍，包括半衰期短、脱靶积累倾向、对血液酶失活的敏感性、对患者安全的担忧以及与扩大规模相关的高昂成本。作为克服这些障碍的一种手段，我们建议开发负载 miRNA 的 Tat-A86 纳米颗粒，因为 Tat-A86 能够保护负载剂免受外部环境因素的影响，减少降解和失活，同时延长循环时间和靶向积累。基因工程 Tat-A86 具有 16 个拷贝的白细胞介素 4 受体 (IL-4R) 结合肽 (AP1)、用于肿瘤渗透的 Tat 以及用于呈递目标配体并确保稳定性的弹性蛋白样多肽 (ELP)，作为该输送系统的基础。使用包括 Tat-E60 和 A86 在内的比较组来辨别结合和渗透的差异。设计的基于ELP的纳米颗粒Tat-A86有效地凝聚了miRNA，在生理条件下形成稳定的纳米复合物。 miRNA/Tat-A86 制剂特异性结合肿瘤细胞，促进稳定的 miRNA 递送至肿瘤细胞内，有效抑制肿瘤生长。使用刘易斯肺癌（LLC）三维球体作为体外模型和LLC荷瘤小鼠作为体内模型进一步评估miRNA/Tat-A86的功效。研究发现，miRNA/Tat-A86 通过显着提高 miRNA 渗透性来促进有效的细胞杀伤，从而导致 LLC 球体尺寸大幅减小。与其他对照相比，Tat-A86 在抑制 3D 细胞聚集体的生长方面表现出卓越的功效。此外，在同等剂量下，Tat-A86 递送的 miRNA-34a 抑制同种异体移植小鼠中 LLC 细胞的生长。总体而言，这些研究表明 Tat-A86 纳米颗粒可以系统性递送 miRNA，通过促进 miRNA 克服阻碍 miRNA 递送的基本障碍吸收和稳定性，最终改善治疗效果。© 2024。作者。

The exogenous delivery of miRNA to mimic and restore miRNA-34a activity in various cancer models holds significant promise in cancer treatment. Nevertheless, its effectiveness is often impeded by challenges, including a short half-life, propensity for off-target accumulation, susceptibility to inactivation by blood-based enzymes, concerns regarding patient safety, and the substantial cost associated with scaling up. As a means of overcoming these barriers, we propose the development of miRNA-loaded Tat-A86 nanoparticles by virtue of Tat-A86's ability to shield the loaded agent from external environmental factors, reducing degradation and inactivation, while enhancing circulation time and targeted accumulation.Genetically engineered Tat-A86, featuring 16 copies of the interleukin-4 receptor (IL-4R)-binding peptide (AP1), Tat for tumor penetration, and an elastin-like polypeptide (ELP) for presenting target ligands and ensuring stability, served as the basis for this delivery system. Comparative groups, including Tat-E60 and A86, were employed to discern differences in binding and penetration. The designed ELP-based nanoparticle Tat-A86 effectively condensed miRNA, forming stable nanocomplexes under physiological conditions. The miRNA/Tat-A86 formulation bound specifically to tumor cells and facilitated stable miRNA delivery into them, effectively inhibiting tumor growth. The efficacy of miRNA/Tat-A86 was further evaluated using three-dimensional spheroids of lewis lung carcinoma (LLC) as in vitro model and LLC tumor-bearing mice as an in vivo model. It was found that miRNA/Tat-A86 facilitates effective cell killing by markedly improving miRNA penetration, leading to a substantial reduction in the size of LLC spheroids. Compared to other controls, Tat-A86 demonstrated superior efficacy in suppressing the growth of 3D cellular aggregates. Moreover, at equivalent doses, miRNA-34a delivered by Tat-A86 inhibited the growth of LLC cells in allograft mice.Overall, these studies demonstrate that Tat-A86 nanoparticles can deliver miRNA systemically, overcoming the basic hurdles impeding miRNA delivery by facilitating both miRNA uptake and stability, ultimately leading to improved therapeutic effects.© 2024. The Author(s).