Multifunctional Magnetothermo-Responsive Smart Hydrogel for On-Demand Controlled Drug Release in Cancer Therapy

Targeted and on-demand drug delivery technologies have attracted considerable interest for personalized cancer therapies. In this study, we developed a UV-crosslinkable and thermo-responsive gelatin methacrylate (GelMa)-poly(N-isopropylacrylamide) (PNIPAM) (G/P) hybrid hydrogel, integrated with folic acid-functionalized superparamagnetic iron oxide nanoparticles (SPIONs). Differential scanning calorimetry (DSC) and alternating magnetic field (AMF) evaluations confirmed that introducing GelMa modulated the lower critical solution temperature (LCST) to approximately 32 °C while enabling efficient magnetothermal response. Cyclic compression tests demonstrated superior mechanical properties. The 2.5G/P hydrogel achieved a compressive strength of 0.06 MPa at 78% strain, outperforming pure GelMa (0.023 MPa) and PNIPAM (0.012 MPa), with the highest modulus of elasticity at both 25 and 37 °C. In vitro biocompatibility assays using L929 fibroblasts indicated excellent cytocompatibility with >70% viability over 7 days. Furthermore, the hydrogel demonstrated excellent blood compatibility with a hemolysis ratio below 2%, complying with ISO 10993-4 standards. Synergistic reduction in cell viability was observed in human lung adenocarcinoma (NCI-H1975) and fibroblast-like osteosarcoma (MG-63) cell lines when combining drug loading and simulated AMF thermal stimulation. Triggered by hyperthermia at 41 °C, the hydrogel demonstrated a highly controlled, pulsatile 'ON/OFF' drug release profile of 5-fluorouracil (5-FU) driven by network shrinkage, achieving a maximum cumulative release of 72.6% over 28 days with a well-defined biphasic kinetic pattern. These results show that this dual-stimuli responsive hydrogel is a mechanically robust, highly efficient platform for controlled cancer therapy.