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.
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