通过益生菌的CRISPR-Cas系统进行光热敏感免疫治疗时,深入肿瘤穿透是必要条件。
Deep Tumor Penetration of CRISPR-Cas System for Photothermal-Sensitized Immunotherapy via Probiotics.
发表日期:2023 Aug 24
作者:
Wen Luo, Zhibin Zhang, Dongtao Zhou, Yateng Jiang, Jingjing Yang, Bangshun He, Haijia Yu, Yujun Song
来源:
Cell Death & Disease
摘要:
由于实体肿瘤中央细胞更为恶性和侵袭性,改善治疗药物的穿透能力并在肿瘤中心激活免疫反应对癌症治疗具有巨大潜力。在这里,通过负载CRISPR-Cas9质粒的脂质体(Lipo-P)包裹聚多巴胺在表面的大肠杆菌Nissle 1917(EcN),实现了在深部肿瘤中同时激活先天和适应性免疫反应的强化免疫治疗。经由靶向缺氧积累于肿瘤中心后,Lipo-P可以在活性氧(ROS)响应性链释放下分离,通过Hsp90α蛋白耗竭降低癌细胞的热阻抗。借此,当近红外辐照引发的聚多巴胺加热时,可实现有效的肿瘤消融。此外,轻度的光热疗法能够诱导免疫细胞凋亡,作为肿瘤组织中的细菌感染引发先天免疫反应的方式。这种利用细菌辅助的方法在深部肿瘤中提供了有前景的光热灵敏免疫治疗方案。
Since central cells are more malignant and aggressive in solid tumors, improving penetration of therapeutic agents and activating immunity in tumor centers exhibit great potential in cancer therapies. Here, polydopamine-coated Escherichia coli Nissle 1917 (EcN) bearing CRISPR-Cas9 plasmid-loaded liposomes (Lipo-P) are applied for enhanced immunotherapy in deep tumors through activation of innate and adaptive immunity simultaneously. After accumulation in the tumor center through hypoxia targeting, Lipo-P could be detached under the reduction of reactive oxygen species (ROS)-responsive linkers, lowering the thermal resistance of cancer cells via Hsp90α depletion. Owing to that, heating induced by polydopamine upon near-infrared irradiation could achieve effective tumor ablation. Furthermore, mild photothermal therapy induces immunogenic cell death, as bacterial infections in tumor tissues trigger innate immunity. This bacteria-assisted approach provides a promising photothermal-sensitized immunotherapy in deep tumors.