长链非编码 RNA 靶向生物支架介导的三重免疫效应用于结直肠癌术后免疫治疗。

LncRNA-targeting bio-scaffold mediates triple immune effects for postoperative colorectal cancer immunotherapy.

机构信息

Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

出版信息

Biomaterials. 2022 May;284:121485. doi: 10.1016/j.biomaterials.2022.121485. Epub 2022 Mar 24.

DOI:10.1016/j.biomaterials.2022.121485

PMID:35367839

Abstract

Colorectal cancer (CRC) recurrence after surgical resection results in poor clinical outcomes. Long noncoding RNAs (lncRNAs) are emerging new targets for mediating tumorigenesis and immunosuppression within tumor microenvironment. We develop a bio-scaffold encapsulating lncRNA-targeting biomimetic nanosystems for mediating triple immune effects against postoperative CRC recurrence. Liposome (termed as "D")-decorated CRC cells' membrane (CM) envelops a plasmid encoding a short hair-pinned RNA (shRNA) against plasmacytoma variant translocation 1 (Pvt1), forming the shPvt1-CM-D nanosystem. This nanosystem and the chemodrug Oxaliplatin (Oxa) are embedded in a hyaluronic acid and alginate-based bio-scaffold for postoperative implantation. (1) ShPvt1-CM-D-mediated Pvt1 knockdown strengthens Oxa-induced immunogenic cell death (ICD). (2) Such tumor antigens released from enhanced ICD and the CM from shPvt1-CM-D act as dual vaccines of dendritic cells. (3) Pvt1 knockdown by shPvt1-CM-D within granulocytic myeloid-derived suppressor cells (G-MDSCs) ameliorates G-MDSC-mediated immunosuppression. The nanosystem-carrying bio-scaffold significantly suppresses perioperative CRC local recurrence by 97.8% with survival rate (SR) of 62.5%. The bio-scaffold generates robust immune memory responses for completely suppressing tumor ectopic rechallenging and metachronous metastasis (SR: 100%). Additionally, the bio-scaffold reduces synchronously distant metastasis by 70.8%. This work presents a potent nanotechnology-facilitated lncRNA-targeting immunotherapy for postoperative CRC treatments.

摘要

结直肠癌（CRC）手术后的复发导致了不良的临床结果。长链非编码 RNA（lncRNA）是肿瘤微环境中介导肿瘤发生和免疫抑制的新兴新靶点。我们开发了一种生物支架，该支架包封了针对 lncRNA 的仿生纳米系统，用于介导针对术后 CRC 复发的三重免疫效应。脂质体（称为“D”）修饰的 CRC 细胞的细胞膜（CM）包裹编码针对浆细胞瘤变异易位 1（Pvt1）的短发夹 RNA（shRNA）的质粒，形成 shPvt1-CM-D 纳米系统。该纳米系统和化疗药物奥沙利铂（Oxa）被嵌入透明质酸和藻酸盐基生物支架中，用于术后植入。（1）shPvt1-CM-D 介导的 Pvt1 敲低增强了 Oxa 诱导的免疫原性细胞死亡（ICD）。（2）从增强的 ICD 释放的这些肿瘤抗原和来自 shPvt1-CM-D 的 CM 充当树突状细胞的双重疫苗。（3）shPvt1-CM-D 内粒细胞髓源性抑制细胞（G-MDSC）中的 Pvt1 敲低减轻了 G-MDSC 介导的免疫抑制。纳米系统携带的生物支架可将围手术期 CRC 局部复发率降低 97.8%，生存率（SR）为 62.5%。该生物支架产生了强大的免疫记忆反应，可完全抑制肿瘤异位再挑战和异时性转移（SR：100%）。此外，该生物支架将同步远处转移减少了 70.8%。这项工作提出了一种强大的纳米技术辅助 lncRNA 靶向免疫疗法，用于术后 CRC 的治疗。