Chemical and Biomolecular Engineering - Theses
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ItemEngineering of DNA Micro- and Nanoparticles: Towards Vaccine Delivery( 2021)Vaccines are an effective tool for preventing and controlling various diseases by inducing adaptive immunity. Nanomaterials play an important role in vaccine development. Micro- and nanocarriers can be engineered to improve the therapeutic efficacy of vaccines by (i) preventing the degradation and systemic clearance of vaccine antigens and (ii) facilitating the uptake of vaccines in antigen-presenting cells (iii) co-delivering adjuvants and antigens at desired intracellular compartments for optimal immunotherapy. However, it is important to engineer a carrier that is both effective and safe. Micro- and nanoparticles based on DNA have shown great potential for biological applications, owing to the programmable sequences, predictable interactions, versatile modification sites, and high biocompatibility of DNA strands. This thesis aims to develop facile strategies to synthesize DNA particles for vaccine delivery by self-assembly approaches. First, a simple strategy to synthesize DNA microcapsules is reported. The cytosine-phosphate-guanosine oligodeoxynucleotides (CpG) motif is an efficient vaccine adjuvant that can effectively stimulate the immune system to secrete cytokines. By loading and crosslinking Y-shaped DNA building blocks (containing CpG motifs) into sacrificial calcium carbonate templates, monodisperse and spherical DNA capsules were obtained. These DNA microcapsules were internalized into cells efficiently, accumulated in endosomes, and induced immune cells to secrete high-level of cytokines. Next, we developed a template-assisted and versatile approach for synthesizing a new set of multifunctional particles through the supramolecular assembly of tannic acid (TA) and DNA molecules. Uniform and stable DNA-TA particles with different morphologies could be easily synthesized by using different types of DNA strands. Intriguingly, different DNA sequences can be encoded into this DNA-TA particle for applications in immunotherapy or gene delivery. The incorporation of CpG motifs and ovalbumin into the particles allows the intracellular antigen/adjuvant co-delivery to amplify cytokines production in macrophages, through synergistic effects. In addition, green fluorescent protein (GFP)-expressing plasmid DNA could be transfected by using the DNA-TA particles in HEK293T cells. Finally, nanometer-sized particles were engineered by exploiting the one-pot supramolecular assembly of TA, DNA, and PEG for intracellular delivery of CpG motifs. TA-DNA-PEG nanoparticles with different sizes could be fabricated by adding different molecular weight PEG chains. TA-DNA nanoparticles with tunable size were also synthesized by varying the molar ratio of TA and DNA. The obtained nanoparticles can enhance the cellular uptake of CpG oligonucleotides and consequently the production of cytokines in macrophages. Overall, the engineered DNA-based particles have potential for co-delivering nucleic acids and protein antigens in immune cells to enhance the immunological response against infectious diseases and cancer.
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ItemPolyphenol-inspired engineering of multifunctional films and particles( 2016)Polyphenols, these plant-derived natural products, were traditionally referred to as “vegetable tannins”, due to their original use in the industrial process of “tanning” to convert animal hide into leather. From the 19th century onwards, “real chemistry” got involved in the study of polyphenols, and in the following 100 years, the study of polyphenols has drawn great interest in broad areas of research, including food science, pharmaceutical research, biology, and the original leather manufacturing. However, most of the research on polyphenols is limited to traditional fields, or focuses on the properties of polyphenols in solution. This thesis focuses on exploring the unique physicochemical and biological properties of polyphenols to serve as an important source of inspiration in the search for new and improved materials. A library of functional metal-phenolic network (MPN) nanostructured films and capsules was prepared from the coordination between a phenolic ligand and a range of metal ions. The functional properties of the MPN materials were tailored for advanced drug delivery, positron emission tomography (PET), magnetic resonance imaging (MRI), fluorescence, and catalysis. Furthermore, the engineering of MPN materials into nanoporous replica particles was used as a novel ultrasound imaging probe and therapeutic to detect and decrease endogenous reactive oxidative species, H2O2, in biological systems. By exchanging the previously used multivalent coordination chemistry with dynamic boronate covalent chemistry, biologically relevant, dual-responsive boronate-phenolic network (BPN) capsules that combine the pH responsiveness of MPN with the cis-diol responsiveness of boronate complexes were synthesized. Polyphenol-inspired particle functionalization was later discovered to facilitate an interfacial molecular interaction-induced self-assembly process. This allowed for the generation of a highly versatile and effective methodology to prepare a large variety of superstructures assembled from a wide range of building blocks. This method displayed significant versatilities of sizes, shapes, microstructures, and compositions as building blocks. The generic nature of this method led to a large family of modularly assembled superstructures including core-satellite, hollow, and hierarchically organized supraparticles. Colloidal-probe atomic force microscopy and molecular dynamics simulations provided detailed insight into the role of this polyphenol-based particle functionalization and how this functionalization facilitated superstructure construction.