Biomolecular Stability and Clinical Translation of DNA-based Nanomaterials.

The emerging field of DNA nanotechnology is one of the most promising nano-engineering methods with impact ranging from nano-rulers, logic-gated therapeutics and in-situ transcription devices. Unfortunately, the technology is limited by general stability, charge and unknowns on intracellular fate. With ERC Starting Grant InActioN, aiming to push DNA as functional therapeutic material, I took a deep dive into exploring the engineering parameters that affect the clinical cell-material interface. Following pioneering work on the biostability challenges during my postdoc [N. Ponnuswamy, 2017],

I continued to mark our position as experts of cellular uptake of DNA origami through exploring the effects of nanogeometry and surface parameters [M.M. Koga, 2022].

I have been invited to write in-depth reviews and book chapters on this topic [H. Bila, 2019].

Our contributions to the field have been widely recognized and the strategies adopted as experimental common practice. My efforts have allowed DNA to become a serious candidate for solving clinical challenges and future therapeutic applications [J. Weiden, 2021].

MEDUSA: Multivalent Evolution of DNA-based Supramolecular Assemblies.

Many viral surface proteins are homo-oligomers that present multiple binding sites in a defined spatial geometry. Remarkably, to identify new clinical binders, affinity-enrichment techniques, mainly SELEX (Systematic Evolution of Ligands by Exponential Enrichment), use a monovalent library of potential binders. Unfortunately, monovalent binders often lose their efficacy when multimerized on nanoparticles, yielding non-functional interactions and a need to up dosage for a desired therapeutic outcome, risking side-effects and/or toxicity. Building on my expertise on geometrically-controlled multivalent nanomaterials, I developed a method that capitalizes on a target-defined valency and pattern. The (patented) MEDUSA technology [A. Kononenko, 2025] includes a modular target-tailored central scaffold in the pool of candidate-binders prior to affinity selection.

Binders will therefore evolve directly in the context of target-matching multivalent patterns, which strongly augments their cooperativity and selectivity. Our technology leverages the natural paradigm of molecular co-evolution within multivalent assemblies to create a simple and tuneable platform for discovering multivalent nucleic acid-based binders that cannot be obtained through monovalent SELEX, to any new clinically relevant multivalent target.