Interfacing DNA nanotechnology with biological systems

Deoxyribonucleic acid (DNA) has evolved in nature to store and transfer the genetic information of all life on earth.The fidelity of information processing relies on the precise pairing through noncovalent interactions of a molecular code consisting of four unique nucleobases.By using this programmability DNA can be taken of a biological context and used as building material for the programmable assembly of nanostructures.The routine automated synthesis of DNA has allowed researchers to explore many different DNA architecture designs and applications leading to the creation of the diverse field now termed DNA nanotechnology.DNA nanotechnology has generated many examples of scaffolds, cages, and networks able to precisely position molecules for applications in therapeutics, diagnostics, light harvesting devices, nanopatterning and even molecular computing.The objective of this thesis is to expand the interface between DNA nanotechnology and biological systems.In this way, DNA nanostructures can be used as modular platforms for the design of cellular probes and drug delivery vehicles.We focus our efforts on examining DNA and lipid bilayer interactions as well as increasing DNA nanostructure serum stability.Chapter 1 of this thesis discusses the origins and evolution of the field of DNA nanotechnology and focuses on specific examples within all three major divisions of this field.Chapter 2 describes our work investigating spherically supported bilayers as a platform to land and reversibly assemble DNA cages.This work examines the dynamic addressability of the cages on bilayers, their diffusion properties and depth of anchored cages, and the bilayer templated assembly of DNA structures.Chapter 3 investigates the selective deposition of DNA tile networks on saturated and unsaturated supported lipid bilayers using three structurally different hydrophobic anchors.It is shown that correct network assembly only occurs with compatible packing between the DNAanchor and the lipid alkyl chains.The variation of the anchor and bilayer chemistry generates switchable network morphologies and filamentous materials.Chapter 4 describes our research towards improving the serum stability of DNA nanostructures, using a combination of folding topology and small synthetic end modifications to the DNA.This work uses a DNA triangular prism cage formed from three DNA strands.It is shown that the folded architecture of these cages and small chemical modifications on the DNA ends significantly stabilize the single stranded DNA and the final cages from fetal bovine serum degradation.We also show how this cage can be fully IV ligated to create a closed structure with the highest observed serum stability.These projects intend to demonstrate new ways in which DNA nanotechnology can be applied to biological systems for both medicinal and material based applications.Résumé L'acide désoxyribonucléique (ADN) a évolué dans la nature afin de stocker et transférer l'information génétique de toute vie sur terre.La fidélité du traitement de l'information dépend de la précision de l'appariement, par interactions non-covalentes, d'un code moléculaire consistant de quatre bases azotées uniques.L'utilisation de cette programmation permet à l'ADN d'être sorti de son contexte biologique et d'être utilisé en tant que matériau de construction pour l'assemblage programmé de nanostructures.La synthèse automatisée de l'ADN, maintenant routinière, a permis aux chercheurs d'explorer différents designs architecturaux en ADN et leurs applications, ce qui a mené à la création du domaine de recherche très diversifié maintenant appelé nanotechnologie en ADN.La nanotechnologie en ADN a généré de nombreux exemples de structures, cages, objets en trois dimensions et réseaux, capables de positionner précisément des molécules ayant des applications thérapeutiques, diagnostiques, comme dispositifs de collecte de lumière, en « nanopatterning » et même comme ordinateurs moléculaires.L'objectif de cette thèse est l'expansion des méthodes par lesquelles la nanotechnologie en ADN peut être interfacée avec des systèmes biologiques.De cette façon, la nanotechnologie en ADN peut être utilisée en tant que plateforme modulaire pour le design de sondes cellulaires et de véhicules de livraison.Nous concentrerons nos efforts sur l'examen des interactions entre l'ADN et les bicouches lipidiques de même que sur l'amélioration de la stabilité dans le sérum des nanostructures d'ADN.Le chapitre 1 de cette thèse discute des origines et de l'évolution du domaine d'étude de la nanotechnologie en ADN et se concentre sur des exemples spécifiques contenus dans les trois divisions majeures de ce domaine de recherche.Le chapitre 2 décrit notre travail d'investigation sur les bicouches sphériques supportées en tant que plateformes pour faire atterrir et assembler de façon réversible des cages d'ADN.Ce travail examine l'adressage dynamique des cages sur les bicouches, leurs propriétés de diffusion et la profondeur de l'ancrage des cages et l'assemblage guidé par les bicouches de structures d'ADN.Le chapitre 3 investigue la déposition sélective de réseaux de tuiles d'ADN sur des bicouches lipidiques supportées saturées et insaturées en utilisant V trois ancres hydrophobiques structurellement différents.Il est démontré que l'assemblage correct des réseaux se produit seulement lors de remplissages compatibles entre l'ADN-ancre et les chaînes alkyles lipidiques.Le changement de l'ancre et de la bicouche génère aussi des morphologies en réseaux changeables et des matériaux filamenteux.S'éloignant des bicouches, le chapitre 4 décrit notre recherche sur l'amélioration de la stabilité dans le sérum des nanostructures en ADN en utilisant une combinaison de topologies de pliement et de petites insertions synthétiques à la fin des brins d'ADN.Ce travail utilise un prisme triangulaire en ADN formé de trois brins d'ADN pour toutes les investigations.Il est aussi démontré que les petites modifications à la fin des brins d'ADN stabilisent de façon significative l'ADN simple-brin et l'architecture choice, I will always be grateful for this.I would like to thank my sister (and Ben) and brother for all their encouragement.I would like to thank Jessica for always supporting, believing in me and laughing at all my jokes (wolf pack on!).Also, I would like to thank my extended family, Les Richards and Les Cyrs for all their support and encouragement.I would like to thank my supervisor Prof. Hanadi Sleiman for her mentorship and creating an environment where creativity and new ideas are encouraged and can be brought to the table for discussion.I would also like to thank Prof. Sleiman for always pushing me to achieve my full potential, it has made me a better scientist.I also need to say thank you for hiring all the right people to make my time in the lab such a great experience!I would like to thank all the faculty and professors in the McGill Chemistry Department that have helped me along way and that I have had a chance to work with over the years.One thing to be said for the McGill Chemistry Department is that once you have joined, you are now part of an amazing community of people, with an incredible diversity of activities and just not enough time to try them all.From the Black Shuck hockey to summer softball, basketball to touch football, BDP to Moondog, bagel hour or the winter classic, defense parties and Thomspon House, or Robbie Burns Day, there is a lot going on.I would like to take the opportunity to thank some of the friends I made along the way.Chris, the journey through the rabbit hole was indeed quite epic, thanks for helping me through it all and showing me how to stay afloat in grad school.Working together taught me a lot about good research work ethic and how to be critical about results.The lab saying, "If a gel looks bad, run it again.If a gel looks good, run it again," appropriately describes out mind-set.Whether on an epic bike ride (and walking home with a flat tire!), a late night jam session in St. Bruno, guest appearances with Moondog, at Black Shuck playoff runs or simply chasing Boomicorns and VII Dragons, I am glad I had a solid partner in crime.I would like to say you were a voice of reason, I would be lying.Thanks.Kai, you are like the little brother I already have!I have complete confidence that one day you will reach your target deadlift weight and make your parents very proud.You always appreciate my most ridiculous of jokes and our conversations are, literally, mind numbing.Thanks for all the encouragement; coming to the band shows for photo ops, giving me back great Christmas presents, hat parties, getting me addicted to protein supplements and translating all those Mandarin menus.You are definitely my boy!I wish you all the dirty beards you could want.In all seriousness, I could not have made it through without good friends, thank you.Tom, the Scottsman, whether it was hockey, music, or brewing we gave everything the "Viking Hammer".Thanks for having my back (literally) while we worked together on some great projects.I will never forget our quest for the ultimate IPA, our "research safaris", your brother's funny names, the Chambly bike ride (I have the scars), the arcane science of temporal exploration and most importantly our highly experimental, research driven brew sessions.I am still amazed at how Canadian Scottsmen turn out to be when you spend five years getting to know them.Jo, not sure who I should thank more, you or Bismark, since you brought him everywhere we went!It was worth it though since he is so good at making friends.Your refined palate led us on many adventures, all the way to Burlington and Weinstein and Gambinos.I most of all would thank you for your quick sense of humour and positive attitude, even when the lab was a dark place for me.Your initiation of Evans room or pic-nick table "think tank" discussions have clarified all of life's mysteries for us, #yolo.Your opi

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