Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these cells and modulating the activity of adjuvants. Here we report an LNP-screening method for the optimization of the type of helper lipid and of lipid-component ratios to enhance the delivery of tumour-antigen-encoding mRNA to dendritic cells and their immune-activation profile towards enhanced antitumour activity. The method involves screening for LNPs that enhance the maturation of bone-marrow-derived dendritic cells and antigen presentation in vitro, followed by assessing immune activation and tumour-growth suppression in a mouse model of melanoma after subcutaneous or intramuscular delivery of the LNPs. We found that the most potent antitumour activity, especially when combined with immune checkpoint inhibitors, resulted from a coordinated attack by T cells and NK cells, triggered by LNPs that elicited strong immune activity in both type-1 and type-2 T helper cells. Our findings highlight the importance of optimizing the LNP composition of mRNA-based cancer vaccines to tailor antigen-specific immune-activation profiles.

脂质纳米颗粒（LNP）可被设计为通过促进抗原呈递细胞对其的摄取、刺激这些细胞的成熟并调节佐剂的活性来增强癌症免疫治疗。在此，我们报告了一种 LNP 筛选方法，用于优化辅助脂质类型和脂质成分比例，以增强肿瘤抗原编码 mRNA 向树突状细胞的递送及其免疫激活特性，从而增强抗肿瘤活性。该方法包括在体外筛选可增强骨髓源性树突状细胞成熟和抗原呈递的 LNP，然后在皮下或肌内递送 LNP 后评估黑色素瘤小鼠模型中的免疫激活和肿瘤生长抑制。我们发现，最有效的抗肿瘤活性，尤其是与免疫检查点抑制剂联合使用时，是由 T 细胞和 NK 细胞协同攻击产生的，LNP 可以在 1 型和 2 型 T 辅助细胞中引发强烈的免疫活性。我们的研究结果强调了优化基于 mRNA 的癌症疫苗的 LNP 组成以定制抗原特异性免疫激活谱的重要性。