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Enhancing immunogenicity and release of in situ-generated tumor vesicles for autologous vaccines

文献类型： 外文期刊

作者： Chen, Jin-hu 1 ; Zhao, Cai-li 1 ; Zhang, Jing 1 ; Cheng, Jia-wen 1 ; Hu, Jian-ping 1 ; Yu, Pei 1 ; Yang, Ming-hua 1 ; Xia, Yuan-zheng 1 ; Yin, Yong 1 ; Zhang, Zhen-zhen 1 ; Luo, Jian-guang 1 ; Kong, Ling-yi 1 ; Zhang, Chao 1 ;

作者机构： 1.China Pharmaceut Univ, Sch Tradit Chinese Pharm, State Key Lab Nat Med, Jiangsu Key Lab Bioact Nat Prod Res, Nanjing 211198, Peoples R China

2.Jiangsu Acad Agr Sci, Inst Vet Med, Nanjing 210014, Peoples R China

关键词： Cancer immunotherapy; In situ vaccination; Tumor-derived extracellular vesicles; Necroptosis; Sialylation/glycosylation; PD-L1; HMGB1

期刊名称：JOURNAL OF CONTROLLED RELEASE （ 影响因子：11.5； 五年影响因子：11.8 ）

ISSN： 0168-3659

年卷期： 2025 年 381 卷

页码：

收录情况： SCI

摘要： In situ vaccination (ISV) strategies offer an innovative approach to cancer immunotherapy by utilizing drug combinations directly at tumor sites to elicit personalized immune responses. Tumor cell-derived extracellular vesicles (TEVs) in ISV have great potential but face challenges such as low release rates and immunosuppressive proteins like programmed death ligand 1 (PD-L1) and CD47. This study develops a nanoparticle-based ISV strategy (Combo-NPs@shGNE) that enhances TEV release and modulates cargo composition. This approach combines Andrographolide, Icariside II, and shRNA targeting UDP-N-acetylglucosamine 2-epimerase/N-ace- tylmannosamine kinase (GNE), which accumulates in the tumor region, resulting in the regulation of immunosuppressive pathways and the reduction of sialic acid production. Decreasing the level of sialylation on the membrane through necroptosis and inhibition of sialic acid synthesis decreased the loading of PD-L1 and CD47 on vesicles, while increasing the loading of heat shock protein 70 and high mobility group box 1 on vesicles, and induced the release of highly immunogenic TEVs from the cancer cells, with a 56.44% release, 9.57 times higher than that of blank nanoparticle-treated cells. In vivo studies demonstrate that Combo-NPs@shGNE enhances TEV yield, tumor growth, reduces metastases, and improves survival in an osteosarcoma mouse model. It promotes dendritic cell maturation, increases CD4+ and CD8+ T cell infiltration, and alters the microenvironment by reducing myeloid-derived suppressor cells and enhancing immunostimulatory factors. Additionally, it transitions tumor-associated macrophages from M2 to an M1 phenotype, thereby augmenting tumor immunity. Overall, Combo-NPs@shGNE offers a promising method for transforming tumors into personalized autologous vaccines, potentially advancing cancer treatment strategies.

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