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Constraining proximity-based drugs, such as proteolysis targeting chimeras (PROTACs), into their bioactive conformation can significantly impact their selectivity and potency. However, traditional methods for achieving this often involve complex and time-consuming synthetic procedures. Here, we introduced an alternative approach by demonstrating DNA-templated spatially controlled PROTACs (DTACs), which leverage the programmability of nucleic acid-based self-assembly for efficient synthesis and offer precise control over inhibitors’ spacing and orientation. The resulting constructs revealed distance- and orientation-dependent selectivity and degradation potency for the Cyclin D1–CDK4/6 protein complex in cancer cells. Notably, the optimal construct DTAC-V1 demonstrated unprecedented synchronous degradation of the entire Cyclin D1–CDK4/6 complex, leading to robust G1-phase cell cycle arrest and effective inhibition of cancer cell proliferation. Furthermore, in a xenograft mouse model, DTAC-V1 exhibited potent therapeutic efficacy by effectively degrading Cyclin D1–CDK4/6 and suppressing tumor growth, underscoring its potential as an anticancer agent. Overall, our findings demonstrate the feasibility of DTAC as a rapid, scalable, and modular platform for the spatial control of functional inhibitors for optimal effectiveness, making it a promising method for proximity-based therapeutics. 

Heuristic algorithms can generalize the design process of stiff and round capsule-like nanostructures made from DNA. 

Abstract The combination of multiple orthogonal interactions enables hierarchical complexity in self‐assembled nanoscale materials. Here, efficient supramolecular polymerization of DNA origami nanostructures is demonstrated using a multivalent display of small molecule host–guest interactions. Modification of DNA strands with cucurbit[7]uril (CB[7]) and its adamantane guest, yielding a supramolecular complex with an affinity of order 10¹⁰m⁻¹, directs hierarchical assembly of origami monomers into 1D nanofibers. This affinity regime enables efficient polymerization; a lower‐affinity β‐cyclodextrin–adamantane complex does not promote extended structures at a similar valency. Finally, the utility of the high‐affinity CB[7]–adamantane interactions is exploited to enable responsive enzymatic actuation of origami nanofibers assembled using peptide linkers. This work demonstrates the power of high‐affinity CB[7]–guest recognition as an orthogonal axis to drive self‐assembly in DNA nanotechnology.