Metal-phenolic networks-encapsulated cascade amplification delivery nanoparticles overcoming cancer drug resistance via combined starvation/chemodynamic/chemo therapy

Multidrug resistance (MDR) of cancer is the main reason for cancer chemotherapy failure, and the use of anticancer drugs usually brings about adverse side effects to patients. Therefore, the aim of developing new cancer treatments must consider overcoming MDR and abating the toxicity of drugs to normal tissues. In this work, we designed and prepared multifunctional cascade amplification delivery nanoparticles (CADNs) with a core structure composed of glucose oxidase (GOx)-attached Fe 3 O 4 nanoparticles, and a shell layer of PEGylated metal-phenolic networks (MPNs), in which the prodrug of doxorubicin (pDOX) was loaded. In vitro assays showed that the MPNs had dual sensitivities to acidic and reducing conditions, and the CADNs promoted the production of hydroxyl radicals in the presence of H 2 O 2 and glucose. Besides, cellular experiments demonstrated that CADNs could efficiently facilitate the accumulation of pDOX in doxorubicin-resistant MCF-7/Adr cells and enhance cancer cell death under the combined action of ferroptosis and chemotherapy. Furthermore, in vivo assays also showed that CADNs with a PEGylated surface could effectively target tumors, and dramatically suppress the growth of both MCF-7 and MCF-7/Adr tumors, with excellent biosafety. This work presents a novel strategy for overcoming cancer MDR by driving cascade reactions to achieve starvation/chemodynamic/chemo combination therapy.