Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
Department of Biomedical Laboratory Science, Konyang University, Daejeon 35365, Republic of Korea.
Int J Pharm. 2024 Sep 5;662:124519. doi: 10.1016/j.ijpharm.2024.124519. Epub 2024 Jul 26.
The use of messenger RNA (mRNA) as a cancer vaccine and gene therapy requires targeted vehicle delivery to the site of disease. Here, we designed a mRNA-encapsulating lipid nanoparticle (LNP) conjugated with anti-programmed death-ligand 1 (PD-L1) DNA aptamer that delivers mRNA encoding a tumor suppressor gene, namely phosphatase and tensin homolog (PTEN), to castration-resistant prostate cancer (CRPC) cells expressing PD-L1 on the cell surface. The DNA aptamer-conjugated LNP-based mRNA delivery system (Apt-LNP[PTEN mRNA]) mediated efficient mRNA delivery and transfection in CRPC cells than LNPs without targeting ligands. Cancer-targeted PTEN mRNA delivery using Apt-LNPs achieved significantly higher PTEN expression via aptamer-mediated endocytosis in target cancer cells compared with non-targeted LNP delivery, resulting in significant downregulation of AKT phosphorylation. This enhanced PI3K/AKT pathway regulation, and in turn reduced cell migration after two days along with a 70 % decrease in cell viability, leading to effective apoptotic cell death. In a CRPC xenograft model, Apt-LNP[PTEN mRNA] led to an approximate 60 % reduction in tumor growth, which was attributable to the effective PTEN restoration and PI3K/AKT signaling pathway regulation. PTEN expression was significantly enhanced in CRPC tumor tissues, which abolished cancer cell tumorigenicity. These findings demonstrated the potential of Apt-LNPs for targeted mRNA delivery to cancer cells, thus providing a promising tool for targeted mRNA delivery to a range of cancers and tissues using a conventional LNP systems.
信使 RNA（mRNA）作为癌症疫苗和基因治疗的应用需要将靶向载体递送到疾病部位。在这里，我们设计了一种包裹 mRNA 的脂质纳米颗粒（LNP），与抗程序性死亡配体 1（PD-L1）DNA 适体缀合，将编码肿瘤抑制基因即磷酸酶和张力蛋白同源物（PTEN）的 mRNA 递送至表面表达 PD-L1 的去势抵抗性前列腺癌（CRPC）细胞。与没有靶向配体的 LNP 相比，DNA 适体缀合的基于 LNP 的 mRNA 递送系统（Apt-LNP[PTEN mRNA]）介导了 CRPC 细胞中 mRNA 的高效递送和转染。Apt-LNPs 介导的靶向 PTEN mRNA 递送至靶癌细胞中的内吞作用导致通过适体介导的内吞作用实现了更高的 PTEN 表达，与非靶向 LNP 递送相比，AKT 磷酸化水平显著下调。这种增强的 PI3K/AKT 通路调节，进而导致细胞迁移减少，两天后细胞活力降低 70%，导致有效的细胞凋亡。在 CRPC 异种移植模型中，Apt-LNP[PTEN mRNA]导致肿瘤生长减少约 60%，这归因于有效的 PTEN 恢复和 PI3K/AKT 信号通路调节。CRPC 肿瘤组织中的 PTEN 表达显著增强，消除了癌细胞的致瘤性。这些发现表明 Apt-LNPs 具有靶向性 mRNA 递送至癌细胞的潜力，从而为使用传统 LNP 系统将靶向性 mRNA 递送至多种癌症和组织提供了有前途的工具。
