DNA-templated spatially controlled proteolysis targeting chimeras for CyclinD1-CDK4/6 complex protein degradation.

Constraining proximity-based drugs, such as proteolysis-targeting chimeras (PROTACs), into its 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, providing precise control over inhibitors' spacing and orientation. The resulting constructs revealed distance- and orientation-dependent selectivity and degradation potency for the CyclinD1-CDK4/6 protein complex in cancer cells. Notably, an optimal construct DTAC-V1 demonstrated the unprecedented synchronous degradation of entire CyclinD1-CDK4/6 complex. This resulted in the effective cell cycle arrest in G1 phase, and further therapeutic studies showed its potent anti-tumor effects compared to inhibitors alone. These findings present a novel framework for PROTACs design, offering critical insights that may inform the development of other proximity-induced therapeutic modalities.

NucleoCraft: The Art of Stimuli-Responsive Precision in DNA and RNA Bioengineering.

Recent advancements in DNA and RNA bioengineering have paved the way for developing stimuli-responsive nanostructures with remarkable potential across various applications. These nanostructures, crafted through sophisticated bioengineering techniques, can dynamically and precisely respond to both physiological and physical stimuli, including nucleic acids (DNA/RNA), adenosine triphosphate, proteins, ions, small molecules, pH, light, and temperature. They offer high sensitivity and specificity, making them ideal for applications such as biomarker detection, gene therapy, and controlled targeted drug delivery. In this review, we summarize the bioengineering methods used to assemble versatile stimuli-responsive DNA/RNA nanostructures and discuss their emerging applications in structural biology and biomedicine, including biosensing, targeted drug delivery, and therapeutics. Finally, we highlight the challenges and opportunities in the rational design of these intelligent bioengineered nanostructures.

Two-Dimensional Excitonic Networks Directed by DNA Templates as an Efficient Model Light-Harvesting and Energy Transfer System.

Photosynthetic organisms organize discrete light-harvesting complexes into large-scale networks to facilitate efficient light collection and utilization. Inspired by nature, herein, synthetic DNA templates were used to direct the formation of dye aggregates with a cyanine dye, K21, into discrete branched photonic complexes, and two-dimensional (2D) excitonic networks. The DNA templates ranged from four-arm DNA tiles, ≈10 nm in each arm, to 2D wireframe DNA origami nanostructures with different geometries and varying dimensions up to 100×100 nm. These DNA-templated dye aggregates presented strongly coupled spectral features and delocalized exciton characteristics, enabling efficient photon collection and energy transfer. Compared to the discrete branched photonic systems templated on individual DNA tiles, the interconnected excitonic networks showed approximately a 2-fold increase in energy transfer efficiency. This bottom-up assembly strategy paves the way to create 2D excitonic systems with complex geometries and engineered energy pathways.