Ionizable lipid nanoparticles (LNPs) have enabled significant advances in oligonucleotide (ON) therapeutics, resulting in the approval of the short interfering RNA (siRNA)-based formulation Onpattro. However, achieving cell-specific delivery remains challenging. We have developed palmitate-containing ionizable LNPs functionalized with (i) octreotide (Oct), targeting somatostatin receptor type 2 (SSTR2)-expressing tumor cells, and (ii) penetratin (RK16), enhancing intracellular uptake. This dually decorated LNP codelivered two siRNAs targeting tumor-promoting genes (heat shock protein 27 (Hsp27) and human epidermal growth factor receptor 2 (HER2)) into HER2+ breast cancer cells, demonstrating strong potential for combinatorial therapies. Oct conferred high selectivity toward SSTR2-overexpresing HER2+ breast cancer cells, even in heterogeneous environments containing nontumor cells. RK16 enhanced intracellular delivery and cytotoxicity against tumor cells compared to nonfunctionalized LNPs. Overall, our results support the potential use of this novel LNP formulation in ON-based targeted therapies. By altering the targeting peptide and siRNA combination, it could be adapted for diverse tumors and combination treatments. Additionally, palmitic acid inclusion further enhanced cytotoxicity in palmitate-sensitive cells, offering additional therapeutic advantages.
