A Functionalized Metal–Organic Framework‐Based Controlled Dual‐Drug Delivery System with Short Hairpin RNA and Simvastatin for Ferroptosis in Colorectal Cancer

Abstract Colorectal cancer is one of the most common causes of cancer‐related deaths worldwide. Ferroptosis is a non‐apoptotic form of regulated cell death that can be triggered by excessive lipid peroxidation and provides an alternative cancer treatment option. To design ferroptosis‐targeted nanomedicine, a new type of nanoparticle is synthesized. The antineoplastic agent simvastatin (SIM) and specifically designed short hairpin RNA (shRNA) are co‐loaded into zeolitic imidazolate framework‐8 (ZIF‐8) nanoparticles coated with poly(carboxybetaine methacrylate) (PCBMA). The constructed shRNA/ZIF‐8@PCBMA‐SIM nanoparticles effectively eliminate human colorectal carcinoma cells in vivo, showing superior cytotoxicity against tumors owing to their improved targeting ability and the high retention of antineoplastic agents delivered at tumor sites. Furthermore, SIM and shRNA downregulate the expression of ferroptosis‐related enzymes 3‐hydroxy‐3‐methylglutaryl‐CoA reductase and glutathione peroxidase 4, thus, triggering ferroptosis in cancer cells. Given that SIM is already approved for clinical use, and shRNA offers high potency to downregulate the cystine/glutamate antiporter (x‐CT) system protein (subunit SLC7A11), shRNA/ZIF‐8@PCBMA‐SIM nanoparticles show great clinical potential to treat colorectal cancer via ferroptosis. This presents an alternative therapy that addresses the limitations of chemotherapy.