Programmable immune activation and antitumor efficacy enabled by spatially encoded biomimetic framework nucleic acids.

Biomimetic materials offer a powerful strategy for precise immune modulation by recapitulating natural biological architectures. However, achieving programmable control of immune functions through nanoscale spatial organization remains a significant challenge. Here, we report a class of 3D framework nucleic acids (FNAs) with precisely defined geometries that enable the ordered co-presentation of antigens and immunoadjuvants via a spatial encoding strategy, thereby systematically regulating immune responses. By constructing tetrahedral, triangular prism, and cubic topologies, we demonstrate that geometric configuration plays a critical role in modulating cellular uptake behavior and dendritic cell (DC) maturation. Among these, the cubic structure exhibits superior cellular internalization efficiency and enhanced antigen cross-presentation capability. In lymph nodes, this biomimetic system significantly increases the proportion of CD11c+ CD86+ DCs and promotes MHC class I-dependent antigen presentation, leading to robust activation of CD8+ T cell-mediated immune responses. In tumor-bearing models, this strategy further enhances immune cell infiltration and reshapes the tumor immune microenvironment, resulting in pronounced tumor suppression and improved survival outcomes. Mechanistically, these effects are attributed to a "spatial encoding-driven receptor clustering mechanism," which mimics the multivalent ligand organization of natural pathogens to promote immune activation. Collectively, this study introduces a structure-information-driven biomimetic immunomodulation strategy, offering a new design paradigm for the development of efficient and safe nanovaccines and immunotherapeutic materials.