Mild hyperthermia-mediated osteogenesis and angiogenesis play a critical role in magnetothermal composite-induced bone regeneration

Mild hyperthermia is greatly beneficial to the healing of bone defects; however, how to generat hyperthermia directly at the bone defect site remains an unsolved problem due to the poor thermal conversion capability of currently commercially available materials and the thickness of soft tissues. Herein, we applied mild magnetic hyperthermia therapy (MHT) to restore critical-sized bone defect using an Arg-Gly-Asp (RGD)-coated, core-shell structured magnetic iron oxide nanoparticle (MION; CoFe₂O₄ @MnFe₂O₄) material to fabricate an optimized osteoinductive nanoparticles-hydrogel composite by embedding the nanoparticles in the agarose with a prominent magnetothermal effect. An alternating magnetic field with strong tissue penetration could evoke a mild MHT (41–42 °C) in the composites, which significantly promoted the osteogenic differentiation and biomineralization of pre-osteoblasts via a heat shock protein (HSP) 90-activated PI3K/Akt pathway. Simultaneously, the cobalt element in the CoFe₂O₄ @MnFe₂O₄ upregulated the expression of the angiogenesis-related gene HIF-1α, which was further promoted under mild heat stimulation. The dual effects notably facilitated the formation of new blood vessels at the lesion. This work demonstrates the great potential of MION-induced mild magnetothermal therapy for the efficient regeneration of critical-sized bone defects.