Nanodelivery of Y-27632 by RGD-modified liposome enhances radioimmunotherapy of hepatocellular carcinoma via tumor microenvironment matrix stiffness reprogramming.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-07-28 eCollection Date: 2025-01-01 DOI:10.7150/thno.114892
Yang Shen, Zihui Zheng, Xinyao Hu, Zhuolin Zhou, Yangtao Xu, Siyu Wang, Shuhong Yu, Xiaoqin He, Ximing Xu
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引用次数: 0

Abstract

Background: Hepatocellular carcinoma (HCC) causes a significant mortality burden worldwide. Radiotherapy (RT) is the primary locoregional treatment modality for HCC. However, the efficacy of RT in HCC is limited by tumor microenvironment (TME) hypoxia, immunosuppression, and extracellular matrix (ECM) stiffness. Methods: We developed a novel RGD-modified liposomal platform (RGD@LP-Y) that encapsulates the ROCK inhibitor Y-27632 through thin-film hydration. We characterized the RGD@LP-Y by the transmission electron microscope (TEM), UV-Vis spectrophotometer, and dynamic light scattering instrument (DLS). A high-stiffness hydrogel co-culture system mimicking mechanical TME was established to explore the role of RGD@LP-Y on matrix stiffness remodeling. In vitro evaluations included cytotoxicity, reactive oxygen species (ROS) generation, mitochondrial function, immunogenic cell death (ICD) markers, and immune cell activation. Mechanistic investigations encompassed matrix stiffness regulation analysis, flow cytometry profiling of pro-inflammatory macrophages, dendritic cell (DC) maturation, transcriptome sequencing, and western blotting. In vivo validation used xenograft models treated with intravenous RGD@LP-Y and localized RT. Biosafety was confirmed through organ histology, serum biochemistry analysis, and hemolysis assay. Results: RGD@LP-Y downregulated matrix stiffness markers (YAP/COL1) and activated PI3K/AKT/NF-κB signaling to drive pro-inflammatory macrophage polarization and DC maturation. The synergistic effects were observed in combination with RT. The treatment of RGD@LP-Y and RT inhibited HCC proliferation, induced apoptosis, suppressed mitochondrial respiration, elevated intracellular ROS, and thus enhanced ICD. In vivo, RGD@LP-Y+RT demonstrated potent tumor suppression and immune activation without systemic toxicity. Conclusion: RGD@LP-Y enhances RT sensitivity by remodeling ECM stiffness, modulating the hypoxia and immunosuppressive conditions within TME, and enhancing the ICD. The study provides a safe combinatorial approach for HCC therapy.

rgd修饰脂质体纳米递送Y-27632通过肿瘤微环境基质刚度重编程增强肝细胞癌放射免疫治疗。
背景:肝细胞癌(HCC)在世界范围内造成严重的死亡率负担。放射治疗(RT)是HCC的主要局部治疗方式。然而,RT在HCC中的疗效受到肿瘤微环境(TME)缺氧、免疫抑制和细胞外基质(ECM)僵硬的限制。方法:我们开发了一种新的rgd修饰脂质体平台(RGD@LP-Y),该平台通过薄膜水合封装ROCK抑制剂Y-27632。利用透射电子显微镜(TEM)、紫外-可见分光光度计和动态光散射仪(DLS)对RGD@LP-Y进行了表征。建立模拟机械TME的高刚度水凝胶共培养体系,探讨RGD@LP-Y对基质刚度重塑的作用。体外评价包括细胞毒性、活性氧(ROS)生成、线粒体功能、免疫原性细胞死亡(ICD)标志物和免疫细胞活化。机制研究包括基质刚度调节分析,促炎巨噬细胞的流式细胞术分析,树突状细胞(DC)成熟,转录组测序和western blotting。体内验证采用静脉注射RGD@LP-Y和局部rt处理的异种移植物模型。通过器官组织学、血清生化分析和溶血试验证实生物安全性。结果:RGD@LP-Y下调基质刚度标志物(YAP/COL1),激活PI3K/AKT/NF-κB信号,推动促炎巨噬细胞极化和DC成熟。RGD@LP-Y与RT联合治疗可抑制HCC增殖,诱导细胞凋亡,抑制线粒体呼吸,升高细胞内ROS,从而增强ICD。在体内,RGD@LP-Y+RT显示出有效的肿瘤抑制和免疫激活,无全身毒性。结论:RGD@LP-Y通过重塑ECM刚度、调节TME内缺氧和免疫抑制状况、增强ICD增强RT敏感性。该研究为HCC治疗提供了一种安全的联合治疗方法。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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