Advancing pharmaceutical technology has made it possible to treat diseases once considered ‘undruggable.’ Access to these new pharmaceutical targets is possible thanks to the advent of protein and nucleic acid therapeutics. Responses to the COVID-19 pandemic, as well as cutting-edge treatments for cancer and multiple sclerosis have centered on these biologic therapies, promising even greater value in the future. However, their utility is limited at a cellular level by inability to cross the plasma membrane. Nanocarrier technologies encapsulate therapeutics and facilitate uptake into the cell but are often trapped and degraded in endosomes. Arginine-functionalized gold nanoparticles (Arg-NPs) provide efficient, direct cytosolic delivery of various co-engineered proteins, including protein-based CRISPR/Cas9 gene editing machinery. Guanidinium-functionalized poly(oxanorbornene)imide (PONI-Guan) polymers replicate key features of Arg-NPs to provide cytosolic delivery of a range of proteins and nucleic acids under physiologically relevant conditions. My work demonstrated the incredible versatility of PONI-Guan nanocarriers, investigating their capacity for long-term storage through lyophilization, incorporation of a multi-component non-covalent delivery complex, and their ability to transfect both small and larger nucleic acids with high efficiency. My work also helped to demonstrate tropism of PONI-Guan nanoassemblies to inflamed lung tissue, providing a powerful approach to treating inflammatory diseases in the lung. This thesis demonstrates a highly versatile, modular polymer platform for the efficient cytosolic delivery of proteins and nucleic acids under physiological conditions and in a wide range of cell types, revealing a powerful direction for translatability in the treatment of pulmonary inflammation
