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

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 internally encoded mRNA, fused with albumin and IL-36 γ , is transcribed and translated. Since albumin prolongs the half-life of the cytokine, IL-36 γ continuously activates neutrophils via the IL-36R receptor on their surface, enhancing their tumoricidal functions and activating other immune cells. Experimental results confirmed that CMNPs effectively activate neutrophils, leading to robust anti-tumor immune responses and tumor growth inhibition. Compared to the control group, CMNPs increased mouse survival rates to 85%. Collectively, the CMNPs vaccine demonstrates broad therapeutic efficacy and remarkable functional diversity, not only improving the effectiveness of immunotherapy but also providing a novel strategy for neutrophil-targeted tumor immunotherapy.

Abstract from PubMed Central (PMID 42979333, PMC13730235). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.