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Limited ability to elicit cellular immune responses has restricted the effectiveness of conventional adjuvants in the context of cancers. Recent advancements in innate immune activation mechanism investigations have paved the way for the implementation of a "bottom‐up" approach in the development of novel adjuvants. Herein, a simple hydrogel adjuvant with a uniformly organized nanoscale microstructure, termed MnPgel is devised, by employing self‐assembling peptides incorporated with manganese ions (Mn2+). MnPgel exhibits Mn2+ sustained‐release properties in vivo and effectively promotes germinal center formation, thereby facilitating the generation of antibodies at levels comparable to conventional aluminum‐based adjuvants. Moreover, MnPgel transcends the scope of humoral immunity, demonstrating the ability to robustly trigger cellular immune responses and positioning it as a promising candidate for cancer prevention and treatments. In conclusion, the work has introduced a well‐defined hydrogel adjuvant as a proof‐of‐concept, simplifying vaccine adjuvant design and opening up new avenues for "on‐demand" immunomodulation strategies. [ABSTRACT FROM AUTHOR]

[Display omitted] • Development of a new self-assemble aromatic peptide (F-AP) platform functional as subunit vaccine adjuvant. • F-AP induces potent antibody titers in mice. • F-AP assists subunit vaccines escape from lysosome and induces dendritic cell differentiation. Compared with vaccines comprising inactivated or attenuated whole pathogens, the subunit vaccines based on protein antigens are safer and easier to manufacture. Yet subunit vaccines usually exhibit weak and nondurable immune responses, which is mainly due to their poor uptake by antigen-presenting cells. To address this issue, we develop a fluorinated aromatic peptide (F-AP), in which electronegativity of fluorine is to enhance its affinity with antigens and ability of transmembrane. In mice model, F-AP demonstrated over 4-fold and 501-fold higher antibody titers than AP and conventional aluminum adjuvant, respectively. Consistent with the antibody responses, F-AP greatly promoted the proliferation of T follicular helper cell and mature B cell. Intriguingly, conventional type 1 dendritic cells (cDC1) were also increased in lymph nodes with F-AP vaccination. And antigens localization experiments showed that F-AP help antigens escape from cell lysosomes, indicating that F-AP could potentially induce cellular immune responses through cDC1′s antigen cross-presentation function. Collectively, the data suggest that simple fluorine group modification on aromatic peptide, F-AP, could improve the immune response of subunit antigens. Thus, fluoridation strategy may provide a novel approach for nanomaterials enhancing the vaccination immune response of vaccines or immunotherapies. [ABSTRACT FROM AUTHOR]