Cationic Liposome Coated Phosphorylated Tyrosine Epitope Imprinted Nanoparticles as a “Direct-Occupancy-Driven” Strategy for Targeted Cancer Therapy

Dysregulated tyrosine phosphorylation drives cancer proliferation directly. Though monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) regulate phosphorylation and suppress tumor growth, they are restricted for broader application because of side effects, including anaphylaxis and acquired resistance. Herein we propose a molecularly imprinted polymer@cationic liposome (MIP@Lip) that occupies a phosphorylated tyrosine epitope directly for cancer therapy. Human epidermal growth factor receptor 2 (HER2) was used as a model target in this work. After incubation with HER2+ cancer cells, MIP@Lip was internalized into lysosomes and subsequently escaped into the cytoplasm via the assistance of the cationic lipid. Subsequently, MIP@Lip directly occupied the phosphorylated tyrosine epitope of HER2, inhibiting its phosphorylation and downstream ERK signaling, suppressing over 80% of HER2+ cancer cell proliferation in vitro and tumor growth in vivo. Collectively, as phosphorylated tyrosine promotes proliferation signals directly, MIP@Lip is a “direct-occupancy-driven” strategy, and it offers a promising alternative to conventional targeted therapy.