Magnetothermal nanocomposite scaffolds with dual stimulation for synergistic drug delivery and cellular modulation in wound healing

Exploring the intricate mechanisms by which hyperthermia influences cellular and tissue behavior presents a significant challenge in tissue engineering. Conventional thermal or physical stimulation alone is limited, often triggering inflammation or biomolecular damage, and current magnetothermal systems primarily deliver heat without addressing synergistic mechano-thermal effects or intrinsic cryoprotection. Here, we report core-shell magnetic nanocomposite (MNC) scaffolds engineered to provide non-invasive, spatiotemporally controlled dual stimulation <i>via</i> magnetic actuator hyperthermia (MAH). The scaffolds integrate Fe₃O₄ nanoparticle actuation with a PCL/PEG matrix to simultaneously generate nanoscale mechanical strain and mild hyperthermia (∼42 °C), enabling enhanced cellular activity and programmable drug release. Comprehensive characterization confirmed tunable mechanics, magnetically induced polymer restructuring, and ciprofloxacin stability under repeated activation. To dissect the underlying mechanisms, we employed a comparative experimental design isolating thermal, mechanical, and dual MAH stimuli. Dual stimulation uniquely activated the HSP70-mediated cytoprotective pathway, as validated by immunofluorescence, western blot, and qPCR, and significantly potentiated antibacterial activity compared to single-mode activation. <i>In vitro</i>, MAH scaffolds promoted synergistic osteogenesis (RUNX2 and ALP) and HUVEC-mediated tubulogenesis, while <i>in vivo</i> they accelerated wound closure by 85% within 14 days, with aligned collagen deposition, complete re-epithelialization, and αSMA⁺ neovascularization. These findings establish the first mechanistic linkage between magneto-mechanical actuation, stress adaptation, antibacterial defense, and tissue regeneration, positioning MNC scaffolds as a transformative dual-stimulation platform for regenerative medicine.