Biomimetic co-delivery of lenvatinib and FePt nanoparticles for enhanced ferroptosis/apoptosis treatment of hepatocellular carcinoma

Abstract

Lenvatinib, endorse as a first-line targeted therapy, has demonstrated efficacy in extending the survival span of individuals afflicted with advanced Hepatocellular carcinoma (HCC). However, its therapeutic effect wears off with time, which is ascribed to the cancer cell's tendency to evade and tamper with its usual modes of action, severely limiting its clinical use. This study devises an innovative therapeutic modality involving the synergistic co-delivery of FePt nanoparticles (NPs) and Lenvatinib via poly lactic-co-glycolic acid (PLGA) NPs encase in HCC cell membranes (Len/FePt@CMP NPs). The investigation explores the mechanism through which Lenvatinib induces ferroptosis in HCC, notably by dampening the glutathione peroxidase 4 (GPX4) through the inhibition of fibroblast growth factor receptor 4. FePt NPs are engineered to enhance the efficacy of ferroptosis and apoptosis for HCC treatment. Concurrently, the incorporation of the cancer cell membrane facilitates the targeted accumulation of NPs at the tumor site, leveraging mechanisms of immune evasion and homologous targeting. This enhances ferroptosis/apoptosis treatment efficacy, triggeres by Len/FePt@CMP NPs, is convincingly demonstrated both in vitro and in vivo. The proposed approach has the potential to redefine HCC therapeutic paradigms by overcoming mono-therapeutic limitations in current clinical treatments, showcasing the improved efficacy of a comprehensive strategy.