Redox-Responsive Functional Iron Oxide Nanocrystals for Magnetic Resonance Imaging-Guided Tumor Hyperthermia Therapy and Heat-Mediated Immune Activation

Magnetic nanoparticle-mediated mild hyperthermia is an emerging approach for tumor treatment and antitumor immune activation. However, the precise delivery of magnetic hyperthermia nanoagents inside tumor for mild magnetic hyperthermia therapy (MHT) via intravenous administration remains challenging. In this study, we developed a tumor microenvironment (TME)-responsive nanosystem based on cleavable methoxypolyethene glycol (mPEG) and transactivator of transcription (TAT) cell-penetrating peptide dual-decorated Fe₃O₄nanocrystals (mPEG@TAT@Fe₃O₄) and utilized it to facilitate effective magnetic resonance (MR) imaging, tumor MHT, and mild heat-mediated immune stimulation. The as-constructed mPEG@TAT@Fe₃O₄exhibited supreme sensitivity to the reducing environment in the TME for detaching the mPEG shell and strongly inhibited the proliferation of tumor cells with exposure to an alternating magnetic field. In vivo experiments in CT26 tumor-bearing mice showed that this nanodelivery system received an enhanced T₂-weighted MR imaging-guided tumor MHT by achieving an 85.5% tumor inhibition rate and induced a magnetic hyperthermia-immune synergistic therapy. Notably, the structure-variable delivery system showed a lower intravenous dosage than previously reported agents at a temperature of 43-44 °C induced by MHT. Together with no obvious agent-related adverse events, our study successfully prepared a promising systemic delivery nanomedicine for MR imaging-guided tumor-targeting MHT and provided an attractive method to turn "cold" tumor to "hot".