ALPPL2-Binding Peptide Facilitates Targeted mRNA Delivery for Efficient Hepatocellular Carcinoma Gene Therapy
ALPPL2-Binding Peptide Facilitates Targeted mRNA Delivery for Efficient Hepatocellular Carcinoma Gene Therapy
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DOI：
10.1002/adfm.202204342
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发表时间：
2022-08-15
影响因子：
19
通讯作者：
Duan, Xingmei
中科院分区：
文献类型：
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作者：
Lei, Sibei;Chen, Xiaohua;Duan, Xingmei
基于mRNA的基因治疗已成为肝细胞癌（HCC）治疗的先进策略。然而，其主要限制之一是缺乏体内递送精度。将HCC细胞与其他组织区分开来对于维持mRNA治疗的高稳定性、积极治疗结果和安全性至关重要。本研究通过噬菌体展示技术，开发了一种新的肝癌特异性肽段HCC 167。结果表明，HCC 167肽可以高亲和力特异性识别包括患者样品在内的多种HCC底物。用HCC 167肽修饰纳米颗粒有助于有效的HCC主动靶向能力。当装载有编码Bims的mRNA时，全身施用的DMP-HCC 167/Bims复合物在包括患者来源的异种移植物的多种模型中有效地抑制HCC进展。此外，ALPPL 2蛋白被鉴定为HCC细胞膜上HCC 167肽的特异性结合受体，揭示了基于HCC 167-ALPPL 2配体-受体复合物的新的主动靶向机制。结合结构也通过计算机辅助建模进行了研究。因此，该研究为基于mRNA的HCC治疗提供了有效的主动靶向策略。
mRNA-based gene therapy has emerged as an advanced strategy for hepatocellular carcinoma (HCC) treatment. However, one of its main limitations is lacking delivery precision in vivo. Distinguishing HCC cells from other tissues is crucial for maintaining the high stability, positive therapeutic outcomes, and safety of mRNA therapeutics. Here, a novel HCC specific peptide HCC167 is developed by phage display. It is shown that the HCC167 peptide can specifically recognize variety of HCC substrates including patient samples with high affinity. Modifying nanoparticles with the HCC167 peptide facilitates an effective HCC active targeting ability. When loading with Bims-encoding mRNA, the systemically administrated DMP-HCC167/Bims complex efficiently suppresses HCC progression in multiple models including patient-derived xenografts. Furthermore, the ALPPL2 protein is identified as a specific binding receptor of the HCC167 peptide on the HCC cell membrane, uncovering a new active targeting mechanism based on the HCC167-ALPPL2 ligand-receptor complex. The binding structure is also investigated by computer-aided modeling. The study hence exhibits a potent active targeting strategy for mRNA-based HCC therapy.