Tian Jihua, Xu Huanyu, Ma Zhijie, Wang Jing, Chen Weihao, Chen Jingshu, Sun Qiuyue, Zhang Ruiping
Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan 030001, PR China.
Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan 030001, PR China.
Eur J Pharm Biopharm. 2025 Jun;211:114714. doi: 10.1016/j.ejpb.2025.114714. Epub 2025 Apr 4.
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.
肝细胞癌（HCC）是全球最常见且致命的恶性肿瘤之一，由于其肿瘤免疫抑制微环境（TIME），治疗选择有限。在此，我们构建了源自肝癌细胞的细胞外囊泡（EVs），以包裹负载雷帕霉素的纳米颗粒（Rapa-EVs）用于精准肝癌治疗。实验结果表明，Rapa-EVs提高了水溶性和稳定性。Rapa-EVs显示出高细胞摄取率，可有效靶向肿瘤组织，促进树突状细胞（DC）成熟，从而激活CD8 + T细胞。它们直接抑制H22细胞增殖，促进巨噬细胞M1极化。Rapa-EVs还使异常肿瘤血管正常化，以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来实现雷帕霉素的选择性递送，同时利用其内在免疫原性来启动抗肿瘤免疫，同时协调雷帕霉素介导的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仿生药物递送与微环境调节相结合的肝癌治疗模式，为克服治疗耐药性和改善患者预后提供了一种变革性方法。
