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

作者：Jinhu Chen, Caili Zhao, Jing Zhang, Jia-wen Cheng, Jianping Hu, Pei Yu, Minghua Yang, Yuan‐Zheng Xia, Yong Ying, Zhenzhen Zhang, Jian‐Guang Luo, Lingyi Kong, Chao Zhang · 发表于：Journal of Controlled Release · 年份：2025 · DOI：10.1016/j.jconrel.2025.113614 · 被引用次数：9 · 研究领域：Immunotherapy and Immune Responses、Extracellular vesicles in disease、Phagocytosis and Immune Regulation

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 -acetylmannosamine 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 microen...