ASGPR-targeted micelles co-delivering lenvatinib and COP1 siRNA for hepatocellular carcinoma via dual-targeting

Hepatocellular carcinoma (HCC) therapy faces significant challenges including poor drug bioavailability and limited gene delivery efficiency. This study developed N-acetylgalactosamine (GalNAc)-functionalized polymeric micelles co-loaded with Lenvatinib (LFT) and small interfering RNA (siRNA) targeting E3 ligase COP1 (RFWD2) (GalNAc@LFT/siRNA-MMs) for the co-delivering of LFT and COP1 siRNA. This combinatory strategy aims to enhance HCC treatment by simultaneously enabling chemotherapy and gene silencing. The nanoplatform was constructed using low-molecular-weight polyethyleneimine (PEI) cross-linked with Pluronic copolymers and surface-modified with GalNAc for asialoglycoprotein receptor (ASGPR)-mediated targeting. Physicochemical characterization revealed spherical nanoparticles (∼187 nm; PDI ∼0.41) with sustained drug release properties. In vitro studies demonstrated preferential uptake in ASGPR-positive HCC cells with enhanced cytotoxicity through apoptosis induction and S-phase cell cycle arrest. COP1 silencing was confirmed at both mRNA and protein levels, sensitizing HCC cells to LFT treatment. In an orthotopic HCC model (n = 5 mice/group), GalNAc@LFT/siRNA-MMs exhibited superior tumor targeting and remarkable antitumor efficacy (73% tumor reduction versus 31% with free LFT). Immunohistochemical (IHC) analysis revealed comprehensive tumor suppression through reduced proliferation (Ki-67), inhibited angiogenesis (CD31), and enhanced apoptosis (Caspase-3), while maintaining excellent biocompatibility. This rationally designed co-delivery system overcomes key limitations of conventional HCC therapy by integrating targeted delivery with combined therapeutic actions, offering a promising approach for improving treatment outcomes in this challenging malignancy.