Self-Assembled Biopolymer Systems in Gene Delivery and NanocompositesPublic Deposited
Biopolymers are polymers synthesized by living organisms. Depending on the monomeric units, biopolymers can be classified as polynucleotides (e.g., DNA and RNA), polypeptides (e.g., protein), polysaccharides (e.g., cellulose) and so on. Biopolymers not only play an essential role in nature, but also have wide applications in various fields of industry due to their biofunctionality, biodegradability, renewability, and sustainability. This dissertation focuses on computational studies of biopolymer systems in two specific fields: gene delivery and nanocomposites.', 'Nanoparticle (NP)-mediated delivery of nucleic acids remains a popular nonviral gene delivery strategy that avoids the potential immunogenic and mutagenic risks associated with viral gene vectors. In spite of its great potential, there exist numerous problems that prevent the clinical usage of nonviral gene delivery systems. Computer simulation can play a crucial role in understanding NP formation as well as the interaction of NP with other materials, and guiding the experimental design of effective gene carriers. All-atom simulations can provide insight into the properties of polymeric gene-delivery carriers by elucidating their interactions and detailed binding patterns with nucleic acids. However, to explore NP formation through complexation of these polymers and nucleic acids and study their behavior at experimentally relevant time and length scales, a reliable coarse-grained model is needed. In Chapter 2, I systematically develop such a model for the complexation of small interfering RNA (siRNA) and copolymers. I compare the predictions of this model with all-atom simulations and demonstrate that it is capable of reproducing detailed binding patterns and dynamics. Since the systematic coarse-grained model accelerates the simulations by one to two orders of magnitude, it will make it possible to quantitatively investigate NP formation involving multiple siRNA molecules and cationic copolymers.', 'Previous research has shown that the shape of NPs formed through complexation of plasmid DNA and copolymers can be tuned, which makes it possible to gain an understanding of their shape-dependent transfection properties. Whereas earlier methods achieved shape tuning through the use of block copolymers and variation of solvent polarity, in Chapter 3, I demonstrate that the same degree of shape control can be achieved through the use of graft copolymers that are easier to synthesize and provide a wider range of parameters for shape control. The simulation work provides insight into the mechanism governing the DNA-contained NP shape variation as well as an effective model to guide the future design of polymeric DNA-delivery vectors.', 'PEGylated polycation/DNA NPs with optimized polyethylene glycol (PEG) length and surface density has been shown to be an effective strategy to enhance colloidal stability and decrease non-specific toxicity of these polymeric gene vectors. However, there is very limited understanding of the effect of PEG terminal groups on the transfection properties', 'of these NPs. Chapter 4 presents the study of transfection activity and cellular uptake of surface-functionalized NPs, which are synthesized through complexation of plasmid DNA and PEG-grafted polyethyleneimine, with two series of PEG terminal groups containing alkyl chains at various length either with or without a hydroxyl terminal group. I employ MD simulations to gain insights into the effect of alkyl chain length on the interactions between surface-functionalized NPs and membranes.', 'Cellulose nanocrystals (CNCs) are promising nanocomposite reinforcing agents due to their exceptional mechanical properties, low weight, and bioavailability. However, there are still numerous obstacles that prevent these materials from achieving optimal performance, including high water adsorption, poor nanoparticle dispersion, and filler properties that vary in response to moisture. Surface modification is an effective method to mitigate these shortcomings. In Chapter 5, I present computational studies of the effect of surface modification on water adsorption and interfacial mechanics of CNCs. This work not only supports previous experimental observations but also provides guidelines for controlling moisture effects in cellulose nanocomposites and nanocellulose films through surface modifications.', 'This dissertation advances the understanding of the polymeric gene delivery NP formation and NP behaviors in the cellular uptake process. The methodology and analytical techniques developed can serve as a framework to study other carriers. The study of surface modification of CNCs is an important first step toward the design of moisture-tolerant CNCâ€“polymer nanocomposites.