Combination therapy based on dual-target biomimetic nano-delivery system for overcoming cisplatin resistance in hepatocellular carcinoma

Abstract The clinical use of cisplatin (DDP) is severely restricted because of nonspecific delivery and the induction of serious systemic toxicity. The limited anticancer drug library and the frequent occurrence of multidrug resistance (MDR) have made monotherapy difficult. Strategies to overcome cisplatin resistance and reduce the long-term use of high-dose medicines, as well as strategies for targeted therapy against hepatocellular carcinoma (HCC) are urgently needed. Previous studies revealed that high NOR1 expression in HCC was associated with drug resistance. Herein, a novel, precise drug/siRNA delivery strategy to realize efficient combination chemotherapy-gene therapy is proposed. To pursue this aim, the dual-targeting nanocarrier system A54-RBCm@NLS-Ag-MOFs/DDP/NOR1 shRNA (AR-NADR) was constructed for the treatment of cisplatin resistance in HCC. The core of the nanocarrier system is the NLS peptide-modified Ag-MOFs (NA) synthesized by silver ion (Ag+) and L-histidine loaded with cisplatin and NOR1 shRNA (NADR). The shell part is the A54 peptide inserted into the erythrocyte membrane (AR). Our results show that AR-NADR has efficient internalization by tumor cells owing to its specific binding to the A54 receptors that are abundantly expressed on the surface of HCC cells and the NLS peptide-mediated pathway of nuclear entry. Simultaneously, as a novel smart pH-sensitive nanodrug delivery system (DDS), DDP is more likely to be released in the acidic tumor microenvironment. Moreover, acting as a vector for gene delivery, AR-NADR effectively inhibits tumor drug resistance by dramatically suppressing the expression of NOR1, which induces intracellular DDP accumulation and makes cells sensitive to DDP. Finally, the anti-HCC efficacy and mechanisms of AR-NADR were systematically elucidated by a HepG2/DDP cell model as well as a tumor model. AR-NADR exhibits critical antitumor efficiency and good biocompatibility. Therefore, AR-NADR constitutes a significant strategy to achieve excellent gene silencing efficacy and antitumor efficacy, which provides effective gene therapy and precise treatment strategies for cisplatin resistance in HCC.