A Paramagnetic Metal‐Organic Framework Enhances Mild Magnetic Hyperthermia Therapy by Downregulating Heat Shock Proteins and Promoting Ferroptosis via Aggravation of Two‐Way Regulated Redox Dyshomeostasis

Abstract Mild magnetic hyperthermia therapy (MMHT) holds great potential in treating deep‐seated tumors, but its efficacy is impaired by the upregulation of heat shock proteins (HSPs) during the treatment process. Herein, Lac‐FcMOF, a lactose derivative (Lac‐NH2) modified paramagnetic metal‐organic framework (FcMOF) with magnetic hyperthermia property and thermal stability, has been developed to enhance MMHT therapeutic efficacy. In vitro studies showed that Lac‐FcMOF aggravates two‐way regulated redox dyshomeostasis (RDH) via magnetothermal‐accelerated ferricenium ions‐mediated consumption of glutathione and ferrocene‐catalyzed generation of ∙OH to induce oxidative damage and inhibit heat shock protein 70 (HSP70) synthesis, thus significantly enhancing the anti‐cancer efficacy of MMHT. Aggravated RDH promotes glutathione peroxidase 4 inactivation and lipid peroxidation to promote ferroptosis, which further synergizes with MMHT. H22‐tumor‐bearing mice treated with Lac‐FcMOF under alternating magnetic field (AMF) demonstrated a 90.4% inhibition of tumor growth. This work therefore provides a new strategy for the simple construction of a magnetic hyperthermia agent that enables efficient MMHT by downregulating HSPs and promoting ferroptosis through the aggravation of two‐way regulated RDH.


Figure S1 .
Figure S1.(a) Scanning electron microscope image of FcMOF under a larger field of view.Scale bar: 5 μm.(b) Transmission electron microscopy image of FcMOF under a larger field of view.Scale bar: 200 nm.

Figure S2 .
Figure S2.Photos of FcMOF being attracted by a neodymium magnet in water.

Figure S3 .
Figure S3.Magnetization hysteresis loop of FcMOF in the range of -40 to 40 Oe.

Figure S10 .
Figure S10.The average hydrodynamic diameter of Lac-FcMOF in water, PBS (pH 7.4) and complete 1640 medium.Data are presented as the mean ± SD (n = 3).

Figure S12 .
Figure S12.(a) Time-temperature plots of surface of pork pieces after injection with Lac-FcMOF (20 mg/mL, 100 μL) and BODIPY (100 μg/mL, 100 μL), followed by treatment with alternative magnetic field (coil diameter: 4 cm, frequency: 548 KHz, output power: 3.8 kW) and near-infrared (685 nm, 1 W/cm 2 ) laser light.(b) Infrared thermal images of pork pieces cut from the middle after different treatments.(c) The temperature of each location is indicated by the arrows in (b).

Figure S13 .
Figure S13.UV-Vis spectra of MB in PBS at pH 7.4 (a) and pH 5.0 (b) after different treatments.

Figure S14 .
Figure S14.(a) XPS spectra of Cu 2p orbit for FcMOF.(b) TEM images of FcMOF incubated under different conditions for 48 h.Scale bar: 200 nm.(c) The average hydrodynamic diameter of FcMOF under different conditions at different time points.Data are presented as the mean ± SD (n = 3).(d) Relative Cu release from FcMOF under different conditions within 48 h.Data are shown as the mean ± SD (n = 3).

Figure S18 .
Figure S18.Survival curves of different groups over time.