Development and evaluation of chemical modifications and conjugations for nucleic acid therapeutic delivery

Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are synthetic nucleic acid molecules that could bind complementarily to the specific RNA targets directly or with the aid of specific protein complex before expressing their potent gene silencing effects in different mechanisms of action. These platforms hold great potential for treating a wide range of diseases, including those of previously undruggable targets. However, their applications are hampered by challenges such as low physiological stability, rapid clearance, off-target, and limited cellular internalization. Many efforts have been made by researchers and clinicians to overcome these hurdles. This thesis aims to investigate various approaches to enhance cellular accumulation and uptake of Nucleic Acid Therapeutics, such as the small molecule conjugated DNA nano-scaffold, the short oligonucleotide, and engineered peptide, to improve the overall gene silencing effect. Three projects are studied separately, namely (i) modified G-quadruplex nano-scaffold - a promising antisense oligonucleotides delivery tool for cancer treatments; (ii) oligonucleotide – a potential delivery platform for siRNA; (iii) modified peptide ligands – effective tools for inflammation diagnostic imaging and siRNA delivery. These findings may contribute to the knowledge of ASOs and siRNAs delivery methods and potentially facilitate the future development of these therapeutics.Doctor of Philosoph