免疫佐剂在增强治疗恶性和复发性癌症的治疗性肿瘤疫苗的功效方面起着关键作用。然而，由于对新型佐剂的合理设计和机制理解存在瓶颈，目前临床实践中可用的免疫佐剂非常有限。为推动佐剂设计与开发，本文提出了一种表面拓扑调控策略，用于构建具有改进的佐剂性能的新型佐剂。我们选择具有明确定义的免疫激活分子机制的一种经批准的佐剂核酸CpG寡核苷酸（CpG ODNs）作为材料框架。通过CpG寡核苷酸与二价铁离子之间的协同组装，我们构建了具有不同表面拓扑的免疫刺激CpG纳米颗粒（CpG NPs）。这些自组装的CpG NPs结合了先天免疫的生物和物理激活能力，并可用作恶性肿瘤免疫治疗的肿瘤抗原佐剂。实验结果表明，这些CpG NPs能够迅速进入先天免疫细胞并重构肿瘤微环境（TME），从而通过（i）诱导促炎细胞因子的产生，（ii）促进巨噬细胞从免疫抑制的M2型转变为免疫活化的M1型，（iii）增强成熟树突状细胞（DCs）的抗原呈递，以及（iv）激活肿瘤部位的T细胞来增强抗肿瘤免疫疗效。在所准备的纳米结构中，小球状纳米颗粒（NPpo）作为该佐剂在黑色素瘤模型小鼠中表现出最强的佐剂特性和抗肿瘤免疫治疗效果。总的来说，本研究为设计激活免疫抑制TME的新型佐剂提供了有效的策略，以实现更好的癌症免疫治疗。

Immunoadjuvants play a key role in enhancing the efficacy of therapeutic tumor vaccines for treating malignant and recurrent cancers. However, due to the bottleneck in the rational design and mechanistic understanding of novel adjuvants, currently available immunoadjuvants in clinical practice are very limited. To boost adjuvant design and development, herein we propose a surface topography regulatory strategy for constructing novel adjuvants with improved adjuvant properties. One of the licensed adjuvants with a well-defined molecular mechanism of immune activation, cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs), was used as the material framework. We constructed immunostimulatory CpG nanoparticles (CpG NPs) with different surface topographies by coordination-driven self-assembly between CpG ODNs and ferrous ions. These self-assembled CpG NPs combine the biological and physical activation abilities of innate immunity and can be used as adjuvants of tumor antigens for malignant tumor immunotherapy. The experimental results showed that these CpG NPs could rapidly enter innate immune cells and remold the tumor microenvironment (TME) to enhance anti-tumor immunotherapy via (i) inducing proinflammatory cytokine production; (ii) promoting the transformation of macrophages from immunosuppressed M2 types into immunoactivated M1 types; (iii) amplifying the antigen presentation of mature dendritic cells (DCs), and (iv) activating T cells in tumor sites. Among the prepared nanostructures, pompon-shaped nanoparticles (NPpo) showed the strongest adjuvant properties and anti-tumor immunotherapeutic effect as the adjuvant of ovalbumin in melanoma-bearing mice. Overall, this work provides an effective strategy for designing novel adjuvants for activating the immunosuppressed TME to enable better cancer immunotherapy.This journal is © The Royal Society of Chemistry.