Infected bone defects (IBDs) treatment presents a great challenge in current orthopedics due to the complex nature of these defects, and the diversified demands involving infection control and subsequent bone regeneration. Current-available treatments often fail to address these multifaceted needs effectively. Herein, we propose a cascade magnetic hyperthermia therapy (cMHT) strategy using MNP-PEI-siCkip-1 (MPSC), a magnetogenetic nanoplatform constructed by coating siRNA for casein kinase-2 interacting protein-1 (siCkip-1) and polyethylenimine-carboxylic acid (PEI-COOH) on ZnCoFe(2)O(4)@ZnMnFe(2)O(4) nanoparticles. These MPSCs were then embedded in gelatin methacryloyl (GelMA) to form a nanocatalytic nanoparticle-hydrogel composite (MSG), which exhibited a strong magnetothermal effect. During the disinfection period, the MSG hydrogel generates MHT ( approximately 50 degrees C) under alternative magnetic field (AMF) to destroy dense biofilm, and catalytically produce hydroxyl radicals (*OH) in biofilm microenvironment (BME) for anti-infection. Increased *OH production also promotes the proinflammation regulation of innate immunity for bacteria eradication. After the infection elimination, AMF was tuned to induce mild MHT ( approximately 41 degrees C, mMHT) to promote osteogenesis and suppress excessive inflammation. Gradual MSG hydrogels degradation releases MPSCs, delivering siCkip-1 possessing osteogenic and anti-inflammatory activities to osteoblasts and macrophages. This cascade magnetic hyperthermia therapy (cMHT) strategy offers a compelling solution to the multifaceted challenges of IBD treatment, addressing critical aspects such as infection control and bone regeneration. The innovative approach underscores a promising potential of cMHT as transformative therapeutic option for IBDs, which may lead to improved treatment outcomes.