细胞外囊泡递送雷帕霉素改善肿瘤微环境，增强肝癌免疫治疗。

IF 4.4 2区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutics and Biopharmaceutics Pub Date : 2025-04-04 DOI:10.1016/j.ejpb.2025.114714

Jihua Tian , Huanyu Xu , Zhijie Ma , Jing Wang , Weihao Chen , Jingshu Chen , Qiuyue Sun , Ruiping Zhang

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引用次数: 0

摘要

肝细胞癌（HCC）是全球最常见、最致命的恶性肿瘤之一，由于其肿瘤免疫抑制微环境（TIME），治疗方案十分有限。在此，我们设计了源自肝细胞癌细胞的细胞外载体（EVs），以包裹雷帕霉素负载的纳米颗粒（Rapa-EVs），用于 HCC 的精准治疗。实验结果表明，Rapa-EVs 提高了水溶性和稳定性。Rapa-EVs具有很高的细胞吸收率，能有效靶向肿瘤组织，促进树突状细胞（DC）成熟，从而激活CD8 + T细胞。它们能直接抑制H22细胞增殖，促进巨噬细胞M1极化。Rapa-EVs 还能使异常的肿瘤血管正常化，从而改善药物灌注和免疫细胞浸润，抑制肿瘤转移。这种设计协同利用了 EVs 的天然肿瘤靶向特性，实现了雷帕霉素的选择性递送，同时利用其固有的免疫原性增强了抗肿瘤免疫力，并协调了雷帕霉素介导的 TIME 重塑。通过全面的体外和体内评估，我们的研究建立了一种将生物仿生给药与微环境调节相结合的 HCC 治疗范例，为克服耐药性和改善患者预后提供了一种变革性方法。

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Extracellular vesicles delivered rapamycin to improve the tumor microenvironment and enhance hepatocellular carcinoma immunotherapy

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Extracellular vesicles delivered rapamycin to improve the tumor microenvironment and enhance hepatocellular carcinoma immunotherapy

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies worldwide with limited therapeutic options due to its tumor immunosuppressive microenvironment (TIME). Herein, we engineered extracellular vehicles (EVs) derived from hepatocellular carcinoma cells to encapsulate rapamycin-loaded nanoparticles (Rapa-EVs) for precision HCC therapy. The experimental results demonstrated that the Rapa-EVs improved water solubility and stability. Rapa-EVs showed a high cellular uptake rate and could effectively target tumor tissues, promote dendritic cell (DC) maturation, and thereby activated CD8 + T cells. They directly inhibited H22 cell proliferation, promoted macrophage M1 polarization. Rapa-EVs also normalized aberrant tumor vasculature to improve drug perfusion and immune cell infiltration, inhibited tumor metastasis. This design synergistically harnesses the natural tumor-targeting properties of EVs to achieve rapamycin-selective delivery, concurrently leveraging their intrinsic immunogenicity to prime antitumor immunity while coordinating rapamycin-mediated TIME remodeling. Through comprehensive in vitro and in vivo evaluations, our study establishes a paradigm for HCC therapy that integrates biomimetic drug delivery with microenvironmental modulation, offering a transformative approach to overcome treatment resistance and improve patient outcomes.

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来源期刊

European Journal of Pharmaceutics and Biopharmaceutics 医学-药学

CiteScore

8.80

自引率

4.10%

发文量

211

审稿时长

36 days

期刊介绍： The European Journal of Pharmaceutics and Biopharmaceutics provides a medium for the publication of novel, innovative and hypothesis-driven research from the areas of Pharmaceutics and Biopharmaceutics. Topics covered include for example: Design and development of drug delivery systems for pharmaceuticals and biopharmaceuticals (small molecules, proteins, nucleic acids) Aspects of manufacturing process design Biomedical aspects of drug product design Strategies and formulations for controlled drug transport across biological barriers Physicochemical aspects of drug product development Novel excipients for drug product design Drug delivery and controlled release systems for systemic and local applications Nanomaterials for therapeutic and diagnostic purposes Advanced therapy medicinal products Medical devices supporting a distinct pharmacological effect.