Frontiers in Nucleic Acid Chemistry

Chemical innovation lies at the heart of RNA therapeutic development. Today’s breakthroughs build on decades of foundational research—ranging from novel synthetic strategies to detailed understanding of how chemical modifications influence RNA behavior in biological systems.

Our lab advances the fundamental chemistry of siRNAs to optimize their therapeutic performance. We explore novel backbones and chemical modifications that modulate interactions with Argonaut protein, particularly the PAZ and MID domains, with the goal of improving therapeutic efficacy. We are especially focused on how physicochemical properties—such as size, structure, shape, stability, and lipophilicity—affect siRNA pharmacology.

Efficient RISC loading and precise target recognition are critical for therapeutic function. Different stages of the silencing pathway require specific structural attributes, and we are systematically defining how chemical modifications influence RISC specificity, cleavage kinetics, cooperativity, endosomal escape, tissue retention, and intracellular trafficking.

Another major initiative involves the design of novel conjugates and supramolecular structures. Using rational design and high-throughput screening, we aim to identify functional delivery enhancers—including lipophilic molecules, peptides, sugars, small molecules, and proteins—to maximize therapeutic efficacy.