肿瘤细胞治疗研究
英文原题：Targeting PD-L1 in cholangiocarcinoma using nanovesicle-based immunotherapy.
Targeting PD-L1 in cholangiocarcinoma using nanovesicle-based immunotherapy.
本研究表明，利用生物纳米颗粒递送靶向程序性死亡配体1（PD-L1）的RNA疗法，作为胆管癌（CCA）的治疗策略具有潜力。
本研究证明了利用生物纳米颗粒递送靶向程序性死亡配体1（PD-L1）的RNA治疗药物作为胆管癌（CCA）治疗策略的潜力。RNA治疗药物为细胞内免疫调节提供了前景，但有效的临床转化需要合适的递送策略。牛奶来源的纳米囊泡被修饰以结合上皮细胞黏附分子（EpCAM）适配体，并用于将PD-L1小干扰RNA（siRNA）或Cas9核糖核蛋白直接递送至CCA细胞。在体外，当肿瘤细胞与T细胞或NK 细胞共培养时，纳米囊泡处理降低了CCA细胞中PD-L1的表达，同时增加了脱颗粒、细胞因子释放和肿瘤细胞细胞毒性。同样，在模拟肿瘤微环境的多细胞球体中也观察到了免疫调节作用。与对照组相比，将负载PD-L1 siRNA的靶向治疗囊泡与吉西他滨联合使用，在免疫健全小鼠CCA模型中有效减轻了肿瘤负荷。这项概念验证研究证明了工程化靶向纳米囊泡平台将治疗性RNA货物递送至肿瘤的潜力，以及其在为CCA等难治性癌症生成有效靶向免疫调节疗法中的应用。
This study demonstrates the potential of using biological nanoparticles to deliver RNA therapeutics targeting programmed death-ligand 1 (PD-L1) as a treatment strategy for cholangiocarcinoma (CCA). RNA therapeutics offer prospects for intracellular immune modulation, but effective clinical translation requires appropriate delivery strategies. Milk-derived nanovesicles were decorated with epithelial cellular adhesion molecule (EpCAM) aptamers and used to deliver PD-L1 small interfering RNA (siRNA) or Cas9 ribonucleoproteins directly to CCA cells. In vitro, nanovesicle treatments reduced PD-L1 expression in CCA cells while increasing degranulation, cytokine release, and tumor cell cytotoxicity when tumor cells were co-cultured with T cells or natural killer cells. Similarly, immunomodulation was observed in multicellular spheroids that mimicked the tumor microenvironment. Combining targeted therapeutic vesicles loaded with siRNA to PD-L1 with gemcitabine effectively reduced tumor burden in an immunocompetent mouse CCA model compared with controls. This proof-of-concept study demonstrates the potential of engineered targeted nanovesicle platforms for delivering therapeutic RNA cargoes to tumors, as well as their use in generating effective targeted immunomodulatory therapies for difficult-to-treat cancers such as CCA.
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