Kim Sang Eun, Bak Soyeon, Park Jung Hee, Lee Ji Eun, Lee Yun Ji, Park Min Seok, Ko Soyeon, Choi Hani, Jung Kyung Hee, Na Kun, Hong Soon-Sun
Department of Biomedical Science, Program in Biomedical Science & Engineering, and College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Republic of Korea.
Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Republic of Korea; Department of BioMedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Republic of Korea.
J Control Release. 2025 Aug 10;384:113872. doi: 10.1016/j.jconrel.2025.113872. Epub 2025 May 26.
Receptor-interacting protein kinase 3 (RIP3)-mediated necroptosis has attracted interest as a potential target for cancer therapy as it boosts tumor immunogenicity. Here, we synthesized a pH-sensitive polymer (CA) by conjugating aminopropyl imidazole (API) to chondroitin sulfate (CHS) for RIP3 gene delivery. CA can target cancer cells due to the specific binding ability of CHS to CD44 which is overexpressed in cancer cells. In addition, the introduction of API conferred pH sensitivity, facilitating efficient endosomal escape and enhancing gene delivery efficiency. Increased levels of high mobility group box-1, EEA1, and Rab5 and high activation of RIP3/mixed-lineage kinase domain-like pseudokinase (MLKL) signaling were observed in the CA-shielded RIP3 complex (CA-PEI/RIP3)-treated groups. Significant tumor selectivity and ablation efficacy of CA-PEI/RIP3 were confirmed in A549 xenografts and LLC1 orthotopic lung cancer mouse models. Furthermore, CA-PEI/RIP3-induced necroptotic cell death could enhance the immune response by increasing phagocytosis of dendritic cells (DCs), resulting in large numbers of CD4+ and CD8+ T cells and mature DCs infiltrating tumor tissues and lymph nodes. Collectively, CA-PEI/RIP3 showed significant potential in cancer gene therapy due to the enhanced transfection efficiency and the tumor-targeting properties of CA, providing a safe and robust strategy to activate the immune response for cancer immunotherapy.
受体相互作用蛋白激酶3（RIP3）介导的坏死性凋亡作为一种癌症治疗的潜在靶点已引起关注，因为它能增强肿瘤免疫原性。在此，我们通过将氨丙基咪唑（API）与硫酸软骨素（CHS）偶联来合成一种pH敏感聚合物（CA），用于RIP3基因递送。由于CHS与癌细胞中过表达的CD44具有特异性结合能力，CA能够靶向癌细胞。此外，API的引入赋予了pH敏感性，促进了有效的内体逃逸并提高了基因递送效率。在CA包被的RIP3复合物（CA-PEI/RIP3）处理组中观察到高迁移率族蛋白盒1、早期内体抗原1（EEA1）和Rab5水平升高以及RIP3/混合谱系激酶结构域样假激酶（MLKL）信号的高激活。在A549异种移植瘤和LLC1原位肺癌小鼠模型中证实了CA-PEI/RIP3具有显著的肿瘤选择性和消融效果。此外，CA-PEI/RIP3诱导的坏死性凋亡细胞死亡可通过增加树突状细胞（DC）的吞噬作用来增强免疫反应，导致大量CD4+和CD8+T细胞以及成熟DC浸润肿瘤组织和淋巴结。总体而言，由于CA提高了转染效率并具有肿瘤靶向特性，CA-PEI/RIP3在癌症基因治疗中显示出显著潜力，为激活癌症免疫治疗的免疫反应提供了一种安全且有效的策略。
