Therapeutic inhibitory RNA in head and neck cancer via functional targeted lipid based nanoparticles

The incidence of human papillomavirus (HPV)-induced head and neck cancer is constantly rising and currently there are no specific therapies addressing the distinctive biology HPV-induced cancer approved for clinical use. Short interfering RNA (siRNA) has much potential for therapeutic manipulation of HPV E6/E7 oncoproteins. Naked siRNA molecules, however, are systemically instable and attain limited intracellular penetration. Lipid-based nanoparticles (LNPs) can be utilized for systemic transportation and delivery of siRNA at target site. We recently developed a recombinant protein linker that enables uniform conjugation of targeting antibodies to the LNPs. Herein, we demonstrate the therapeutic efficacy of anti-E6/E7 siRNA delivered via targeted LNPs (tLNPs) in a xenograft HPV-positive head and neck cancer model. We show that anti-epidermal growth factor receptor (EGFR) antibodies, anchored to the LNPs as targeting moieties, facilitate cargo delivery but also mediate anti-tumor activity. Treatment with siE6/E7 via tLNPs resulted in 50% greater reduction of tumor volume compared to treatment with siControl encapsulated in iso-LNPs (LNPs with isotype control antibodies attached to their surface). We demonstrate suppression of HPV oncogenes and higher induction of apoptosis by the tLNPs encapsulating the therapeutic siRNA both in vitro and in vivo. Altogether, the coupling of inhibitory siE6/E7 with anti-EGFR antibodies, that further elicited anti-tumor effects, successfully restricted tumor progression. This system that combines potent siRNA and therapeutically functional tLNPs can be modulated against various cancer models.