Targeting cancer-associated neutrophils with biomimetic nano-vaccines loaded with mRNA can enhance the efficacy of immunotherapy for hepatocellular carcinoma

作者：Songmao Li, Yuhan Zhang, Yueqing Han, Min Zhao, Yi Wang, Jinying Lu, Ran Li, RuiYu Wang, Ruimin Shan, Wenhua You, Hulin Jiang, Judong Luo, Chupeng Hu, Yun Chen · 发表于：Acta Pharmaceutica Sinica B · 年份：2026 · DOI：10.1016/j.apsb.2026.05.002 · 研究领域：Immune cells in cancer、Immunotherapy and Immune Responses、RNA Interference and Gene Delivery

Neutrophils exhibit significant plasticity within the tumor microenvironment (TME), such as promoting immune suppression, tumor growth, and metastasis. Although various nano drug delivery systems targeting neutrophils have been developed based on their tumor chemotaxis, few studies have focused on designing nano-vaccines that specifically target and activate neutrophils to exert anti-tumor effects, mainly due to the lack of specific targets. To address these issues, we genetically engineered tumor cell membranes to first overexpress the CD300LD protein, which was subsequently coated onto the surface of liposomes. Additionally, we encoded and delivered the cytokine IL-36 γ , which can effectively activate neutrophils, thus constructing an mRNA-based biomimetic nanovaccine, termed CMNPs (cell-membrane coated mRNA nanovaccine platform), which is designed to elicit potent anti-tumor immunity by targeted activation of neutrophils. Through analysis of single-cell public databases, we discovered that neutrophils in the TME express CD300LD receptors at significantly higher levels compared to other immune cells. Consequently, we further transduced tumor cells with lentivirus to induce overexpression of the CD300LD protein and utilized cell membrane biomimetic technology to modify the surface of CMNPs. The modified CMNPs can specifically target neutrophils via the extracellular domain (ECD) of the CD300LD protein. Upon targeted delivery of CMNPs to neutrophils in the TME, the internall...