Engineering of a double targeting nanoplatform to elevate ROS generation and DSF anticancer activity

Intracellular oxidative protection mechanisms and adverse systemic toxicity are major obstacles for the success of chemodynamic therapy (CDT)/chemotherapy (CT) synergistic therapy. To tackle the fundamental challenges of current CDT and circumvent the side effects of conventional CT, we developed a copper peroxide (CP) and disulfiram (DSF)-loaded 3-aminotriazole (3-AT) doped ZIF-8 (MAF) with partial sequence-specificity using hyaluronic acid (HA) and triphenylphosphine (TPP) in this study. Upon intravenous administration, CP@MAF-DSF@PEG-TPP@HA (CPMDTH) nanoparticles (NPs) were enriched in tumor tissues through HA-mediated endocytosis, followed by enhanced accumulation in mitochondria by the TPP target. The acidic tumor environment (TME) triggered the decomposition of MAF to release CP, DSF and 3-AT. Cu²⁺ and H₂O₂ hydrated from CP NPs produced ˙OH via a Fenton-like reaction. CAT activity inhibition and GSH consumption induced by 3-AT dramatically amplified mitochondrial oxidative stress, thereby promoting the overproduction of ˙OH. In addition, the accumulation of DSF and Cu²⁺ led to the formation of a cytotoxic bis(N,N-diethyldithiocarbamate) copper(II) complex (Cu(DTC)₂) in situ, achieving efficient CT. CPMDTH NPs demonstrated significantly improved antitumor efficiency and excellent biosafety both in vitro and in vivo. This study offers a promising therapeutic strategy for CDT/CT synergistic oncotherapy.