TIGIT/PVR and LncRNA ANRIL dual-targetable PAMAM polymeric nanoparticles efficiently inhibited the hepatoma carcinoma by combination of immunotherapy and gene therapy

Abstract

Herein, a novel polymeric nanoparticle was designed to inhibit hepatoma carcinoma by simultaneously targeting the T cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor (PVR) and long noncoding RNAs antisense noncoding RNA in the INK4 locus (LncRNA ANRIL). Firstly, the siANRIL-loaded nanoparticles (NP-siANRIL) was developed by methoxy-poly (ethylene glycol)-polyamidoamine (mPEG-PAMAM) and polyamidoamine-poly (ethylene glycol)-disulphide bond-carboxyl (PAMAM-PEG-S2-COOH) using the self-assembly method. Then the DTBP-3 peptide, a newly developed identified peptide which could occupy the binding interface and effectively block the interaction of TIGIT with its ligand PVR, was further conjugated on the surface of NP-siANRIL via the glutathione (GSH)-sensitive disulphide linkage. In this way, the binding ability of DTBP-3 to TIGIT was remained once they were entrapped into the tumour tissues which were abundant of GSH. The present study demonstrated that DTBP-3NP-siANRIL exhibited an excellent anti-tumour effect on hepatoma carcinoma in vivo by simultaneously inhibited the expression of miR-203a and its downstream genes and increased the percentages of NK cells and T cells. In a word, the present study has presented a novel strategy for treatment of hepatoma carcinoma by simultaneously targeting of TIGIT/PVR and LncRNA ANRIL.