Yan Yajuan, Duan Ting, Xue Xiaonan, Yang Xiaojuan, Liu Miao, Ma Bin, Duan Xiangguo, Su Chunxia
School of Basic Medicine, Ningxia Medical University, Yinchuan, People's Republic of China.
School of Inspection, Ningxia Medical University, Yinchuan, People's Republic of China.
Int J Nanomedicine. 2025 Jan 25;20:1047-1063. doi: 10.2147/IJN.S492734. eCollection 2025.
Colorectal cancer (CRC) is a highly malignant and aggressive gastrointestinal tumor. Due to its weak immunogenicity and limited immune, cell infiltration lead to ineffective clinical outcomes. Therefore, to improve the current prophylaxis and treatment scheme, offering a favorable strategy efficient against CRC is urgently needed.
Here, we developed a nanovaccine (LBP-CD155L NVs) loaded with CD155 gene in liposome, which was modified by Lycium barbarum polysaccharides (LBP) through electrostatic interaction. The nanovaccine was characterized by transmission electron microscopy and Zetasizer. It was evaluated in vitro, where NVs facilitated the endocytosis and maturation of DCs, and in vivo, where NVs improved the efficacy of prophylaxis and therapy. In addition, further confirmed the mechanisms by how TLR4 and MGL synergistic pathway endow the nanovaccines towards dendritic cells (DCs). Finally, the safety and tumor immunosuppressive microenvironment were evaluated in the CRC tumor-bearing mouse model.
We successfully developed a nanovaccine that facilitates the endocytosis and maturation of DCs via a synergistic pathway involving TLR4 and MGL, which endow the nanovaccines towards dendritic cells (DCs) and promote the differentiation, thereby enhancing the cytotoxicity of CD8T cells. Consequently, LBP-CD155L NVs can potentiate the efficacy of prophylactic and therapeutic administration in a mouse CRC model, as evidenced by decreased infiltration of myeloid-derived suppressor cells (MDSCs) and Tregs, reprogrammed the macrophage phenotypes, which promoted polarization from M2-like macrophages to M1-like macrophages, increased infiltration of effector T cells. Prophylactic and therapeutic combination regimens with anti-PD-1 treatment demonstrate synergism that stimulates T-cell infiltration into tumors and counteracts immunosuppression, leading to remarkable tumor remission and enhancing the efficacy of immune checkpoint therapy in solid tumors.
Our work provided that LBP-CD155L NVs may serve as a promising tool for reversing tumor immunosuppressive microenvironment and enhancing ICB therapy in CRC.
结直肠癌（CRC）是一种高度恶性且侵袭性强的胃肠道肿瘤。由于其免疫原性弱且免疫细胞浸润有限，导致临床疗效不佳。因此，为改进当前的预防和治疗方案，迫切需要提供一种有效的抗CRC策略。
在此，我们开发了一种脂质体负载CD155基因的纳米疫苗（LBP-CD155L NVs），其通过静电相互作用被枸杞多糖（LBP）修饰。该纳米疫苗通过透射电子显微镜和Zetasizer进行表征。在体外评估其促进树突状细胞（DCs）的内吞作用和成熟，在体内评估其改善预防和治疗效果。此外，进一步证实了TLR4和MGL协同途径赋予纳米疫苗对树突状细胞（DCs）作用的机制。最后，在CRC荷瘤小鼠模型中评估其安全性和肿瘤免疫抑制微环境。
我们成功开发了一种纳米疫苗，其通过涉及TLR4和MGL的协同途径促进DCs的内吞作用和成熟，这赋予纳米疫苗对树突状细胞（DCs）的作用并促进其分化，从而增强CD8T细胞的细胞毒性。因此，LBP-CD155L NVs可增强小鼠CRC模型中预防和治疗给药的效果，骨髓来源的抑制细胞（MDSCs）和调节性T细胞（Tregs）浸润减少、巨噬细胞表型重编程（促进从M2样巨噬细胞向M1样巨噬细胞极化）、效应T细胞浸润增加证明了这一点。抗PD-1治疗的预防和治疗联合方案显示出协同作用，刺激T细胞浸润肿瘤并抵消免疫抑制，导致显著的肿瘤缓解并增强实体瘤中免疫检查点治疗的疗效。
我们的工作表明LBP-CD155L NVs可能是逆转肿瘤免疫抑制微环境和增强CRC中ICB治疗的有前景的工具。
