UC San Diego

Noncovalent assemblies constitute some of the most robust and keystone interactions in biology. Hydrogen bonding, for example, drives hybridization between single DNA strands into double helices for genetic informational storage, while the combination of electrostatic, Van der Waals, and hydrophobic amino acid sequences underpin binding specificity between antibodies and antigens as well as stability in proteins. Similarly, intermolecular forces can yield novel physical, chemical, and optical properties for new materials, such as tunable self-quenching between fluorophores and functionalized surfaces on nanoparticles. Engineered biomolecular self-assembly can thus be a tool to design nanomaterials with specificity to biological events or targets for (1) drug delivery to diseased tissue, (2) signaling for biosensing, or (3) contrast for bioimaging. This dissertation presents strategies for engineered molecular contrast agents and drug delivery platforms using bottom-up bio- and inter-molecular self-assembly pathways. In chapter one, electrostatic interactions establish DNA origami’s ability to cover and disguise the surfaces of herpes simplex virus 1 particles for infection against cancer cells, even when the mammalian strain of the virus is different from the mammalian strain of the host cell. Chapter two outlines the value of enzyme free and isothermal self-assembly between oligonucleotides via strand amplification for resultant signal amplification to detect nucleic acid biomarkers. Chapter three demonstrates this value by presenting strand amplification for triggered contact quenching between NIR fluorophores, leading to enhanced and ratiometric photoacoustic contrast when miR-21 is detected in live cells and within sub-centimeter penetration depths in tissue mimicking phantoms. Chapter four leverages aggregative photoacoustic enhancement when an NIR dye-tagged chemotherapeutic is densely intercalated into a DNA-clad hydrogel for real-time pharmacokinetic tracking. Chapter five examines the resultant geometries from two self-assembly pathways between an engineered tumor-homing peptide and an NIR molecular dye for targeted tumor photoacoustic imaging and targeted photodynamic therapy, underscoring the significance in nanoparticle architecture on resultant interactions with biology at the live cell and live tissue scales.