RNA-DNA Fusomer Fibers With Customizable Physicochemical, Mechanical, and Biological Properties for Next-Generation Therapeutics.

We introduce RNA-DNA fusomers, a new class of chemically synthesized oligonucleotides that combine the versatile properties of RNA and DNA within a single sequence and self-assemble into higher-order functional structures via a simple one-pot annealing reaction. This hybrid platform allows precise customization with therapeutic nucleic acids, offering tunable physicochemical, mechanical, and immunological properties, cost-effective production, and the capacity to integrate biological functionalities intrinsic to both RNA and DNA. The modular architecture of fusomers enables straightforward optimization for diverse biomedical applications, including gene silencing, anti-inflammatory therapy, anticoagulation, antibacterial activity, and protein biosensing. We demonstrate efficient delivery and intracellular modulation by fusomers in multiple model systems, including human peripheral blood mononuclear cells isolated from healthy human donors and 3D organ-on-a-chip models. Molecular dynamics simulations further elucidate the structural behavior of fusomers and their intended interactions with protein targets. Collectively, these findings position fusomers as a next-generation therapeutic platform with broad transformative potential.