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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. 

Abstract DNA origami information storage is a promising alternative to silicon-based data storage, offering a molecular cryptography technique concealing information within DNA origami. Routing, sliding, and interlacing staple strands lead to a large 700-bit key size. Practical DNA data storage requires high information density, robust security, and accurate and rapid information retrieval. Consequently, advanced readout techniques and large encryption key sizes are essential. Here, we report an enhanced DNA origami cryptography protocol in 2D and 3D DNA origami, increasing the encryption key size. We employ all-DNA-based steganography with fast readout through high-speed DNA-PAINT super-resolution imaging. By combining DNA-PAINT data with unsupervised clustering, we achieve an accuracy of up to 89%, despite the flexibility in the 3D DNA origami shown by oxDNA simulation. Furthermore, we propose criteria that ensure complete information retrieval for the DNA origami cryptography. Our findings show that DNA-based cryptography is a secure and versatile solution for storing information.