Selective and Synergistic Targeting of ErbB2-Positive Cancer Cells with ErbB2 Transmembrane Peptide-Ionic Liquid Nanocarrier Formulation.

ErbB2-positive cancers are highly aggressive and remain difficult to treat due to limitations of current therapies, such as poor selectivity, insufficient delivery, and toxicity toward healthy tissues. Herein, we developed a dual-action nanoformulation combining prolinium-based surface-active ionic liquid (SAIL) nanocarriers with ErbB2-derived transmembrane (TM) peptide for selective targeting of ErbB2-positive cancer cells. Two new SAILs, which self-assemble into stable micelles/vesicles under physiological conditions, and a series of hydrophobic TM-peptides were synthesized and characterized. Among the resulting nanoformulations, V3-BAIL showed the strongest antiproliferative activity in ErbB2-positive breast, lung, and pancreatic cancer cell lines, whereas activity in low-ErbB2 NCl-H23 cells was minimal. The response correlated with ErbB2 expression level, demonstrating target-related selectivity. Chou-Talalay analysis revealed synergy between the SAIL nanocarrier and TM peptide. Mechanistic studies showed that V3-BAIL progressively accumulated in cells, reduced cellular fitness without rapid membrane lysis, and strongly suppressed PI3K/Akt and MAPK/ERK signaling. Relative to doxorubicin and cisplatin, V3-BAIL displayed greater selectivity toward ErbB2-positive cells, and it acted more rapidly and more strongly than trastuzumab under the tested conditions. These findings establish TM peptide-decorated SAIL nanocarriers as a promising strategy for selective and synergistic ErbB2-targeted cancer therapy.