DNA Origami-templated Silica nanostructures for applications in biomedicine and catalysis

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Many attempts to explore potential real-life applications of DNA origami have faced the trouble of its inherent instability in non-aqueous conditions or those commonly met within biological environments. On the other hand, Silica nanoparticle research in biomedicine and catalysis has reached a plateau with little new breakthroughs being reported. Here I propose the advancement of both areas by harnessing their combined properties. I will combine structural DNA nanotechnology with materials science in the form of DNA nanostructure-templated Silica nanostructures. DNA origami will be used to create different nanoscale shapes, which will serve as a template for the formation of Silica nanostructures of any desired shape with nanometer-scale precision features, currently not accessible through standard synthesis methods. These structures will be investigated for their cellular uptake mechanism and kinetics and intracellular behaviour for potential downstream therapeutic applications. Adding more functionality to these new Silica nanostructures, DNA origamis will be modified with protruding “handle” strands made from peptide nucleic acids (PNAs). Due to their neutral charge, no Silica deposition can occur on these handles, as this is governed by electrostatic attraction between cationic Silica precursors and the poly-anionic DNA backbone. Therefore after transcription of the DNA origami structure into Silica, PNA handles will protrude from the Silica structure, available for hybridization with other nucleic acids. This results in Silica structures which are fully site-specifically addressable and can be site-specifically modified via nucleic acid hybridization, combining the accurate addressability of DNA origami with the chemical robustness of Silica. These structures will then be utilized both intra- and extracellularly for anti-sense therapy and immunotherapy respectively. By site-specifically positioning tumour necrosis factor superfamily ligands on the Silica surface in a specific geometry (e.g. hexagonally), these can cause cell death by pattern-specific interactions with extracellular death receptors, leading to “cell death by geometry”. Additionally, these novel Silica structures present perfect platforms for the realization of highly efficient enzyme cascades. Harnessing the ability to place a controlled number of different enzymes within a certain distance to one another, with the possibility to do so within the protective “pore” of a silicified DNA origami structure, will allow for enzyme protection and substrate channeling. Furthermore the conjugation of PNA handles positioned around the enzyme with different charged molecules can allow for precise engineering of pH in the local microenvironment around each enzyme. These factors will lead to highly increased catalytic throughput, opening up the possibility to create highly efficient enzymatic nano-factories.