Antisense Oligonucleotide\nEmbedded Context Responsive\nNanoparticles Derived from Synthetic Ionizable Lipids for lncRNA Targeted\nTherapy of Breast Cancer

The long noncoding RNAs (lncRNA) are primarily associated\nwith\nseveral essential gene regulations but are also connected to cancer\nmetabolism and progression. HOTAIR and MALAT1 are two such lncRNAs\nthat are detected in malignancies of various origins and are responsible\nfor the poor prognosis of cancer patients. Due to these factors, the\nlncRNAs have emerged as prime targets for the development of anticancer\ntherapeutics. However, nonviral delivery of lncRNA-targeted antisense\noligonucleotides (ASOs) still remains a critical challenge while maintaining\ntheir structural and functional integrity. Herein, we have designed\nand synthesized a new series of ionizable lipids with variations in\ntheir head groups to prepare lipid nanoparticle (LNP) formulation\nalong with cholesterol-based twin cationic lipid and amphiphilic zwitterionic\nlipid. The context responsiveness of these formulations in delivering\nthe ASOs has been thoroughly investigated by various bioanalytical\ntechniques, and an optimum formulation has been identified. The LNPs\nare utilized to deliver the ASOs targeting HOTAIR lncRNA in human\ncancer cell lines and MALAT1 lncRNA in mouse models. This study thus\nstandardizes an advanced nanomaterial system for nonviral gene delivery\nthat has been validated by a considerable reduction in the target\nlncRNA level under <i>in vitro</i> and a significant reduction\nin tumor volume under <i>in vivo</i> settings.