Nanoscale Micelles Loaded with Fe₃O₄ Nanoparticles for Deep-Tissue Penetration and Ferroptosis/Sonodynamic Tumor Therapy

Large nanoparticles (NPs; >100 nm) can accumulate in the tumor because of the enhanced permeation and retention effect. However, large NPs generally locate next to the blood vessel and are difficult to diffuse within a dense collagen matrix, causing uneven distribution within the tumor. Here, we designed reversibly assembled and disassembled micelles loaded with Fe3O4 and hypocrellin (HC) for ferroptosis and sonodynamic therapy of cancer. Poly(ethylene glycol)–poly(propylene sulfide) (PEG–PPS), an reactive oxygen species (ROS)-responsive amphiphilic polymer, was used to form micelles with Fe3O4 and HC in the core. Upon ultrasound irradiation, ROS was generated by HC for the disassembly of micelles and also for sonodynamic therapy, while realizing a size switch. The released Fe3O4 dissolves to produce Fe2+, which catalyzes hydrogen peroxide to form hydroxyl radicals (•OH). Sonodynamic and ferroptosis therapies generate a synergistic antitumor effect, offering a smart platform for cancer therapy.