In summary, we introduced a novel approach for the preparation of 3D crystalline frameworks with pre-designed structural features and embedded responsiveness, programmable through straightforward design variations. The flexibility of our approach derives from the selfassembly mechanism of amphiphilic C-stars, in which network geometry depends on the general topology and symmetry of DNA motifs, rather than on high-resolution molecular details. This feature enables unprecedented design freedom, that we exploit to produce a set of geometrically identical frameworks with finely controlled lattice parameters spanning a range of nearly 16 nm and reaching a maximum of 34.2 nm. By exploiting the resulting high porosity, the controllable mesh size, and the inherent amphiphilic properties of our material, we are able to fine-tune the partitioning of macromolecules within the frameworks based on size and hydrophobicity. Furthermore, the resilience of the self-assembly mechanism, and the significant free volume available within Cstar networks, allowed us to include a respon- sive DNA motif leading to isothermal dissolution of the frameworks, as well as a chemical modification enabling specific entrapment and triggered release of functional proteins. The structural responsiveness and programmability of the frameworks, combined with their specific and non-specific affinity for various cargoes, hints at the possible application of the material to smart nanomedical vectors. Compared to standard formulations based on lipids, carriers prepared from C-stars could be more easily functionalized with ligands or DNA aptamers to achieve selective targeting of diseased cells, and programmed to dissolve and release their cargo only in the presence of specific molecular cues, e.g. disease-related microRNAs. Critical for this and other biomedical applications is also the resilience of C-star frameworks to low and physiological ionic strength. More complex C-Star variants could also carry nucleic acid complexes designed to amplify signals, perform computation, and respond to molecular and environmental cues, opening a new route for producing highly concentrated, well-ordered, sensing/signal-processing architectures with potential applications in point-ofcare diagnostics, nanomedicine, or bottom-up synthetic biology. Finally, C-star self-assembly occurs in a one-pot reaction, and does not require the use of highly purified oligonucleotides, substantially reducing costs and simplifying preparation protocols compared to other available DNA-tile architectures.