Superparamagnetic Fe3O4 nanoclusters for cancer therapy and metastasis prevention via synergistic chemotherapy and NETs degradation

The overexpression of neutrophil extracellular traps (NETs) serves as a critical biomarker and mediator of tumorigenesis and metastasis. By inhibiting their formation or degrading existing structures, therapeutic strategies targeting NETs have shown promising potential in cancer treatment and metastasis prevention. Deoxyribonuclease I (DNase), while effective in NETs degradation, suffers from rapid plasma clearance, necessitating delivery vehicles to prolong its therapeutic activity. In this study, we developed superparamagnetic Fe 3 O 4 nanoclusters via a one-step solvothermal method for co-delivery of doxorubicin (DOX) and DNase. The resulting nanoplatform demonstrated: (1) enhanced magnetic retention at tumor sites for improved local drug concentration and targeted delivery, and (2) synergistic therapeutic effects under alternating magnetic field (AMF) exposure, combining magnetic hyperthermia with chemotherapy while simultaneously remodeling the tumor microenvironment through NETs degradation. Comprehensive evaluations revealed that this combined approach significantly enhanced antitumor efficacy compared to monotherapies, with the additional benefit of metastasis prevention through tumor microenvironment modulation. This multifunctional nanoplatform thus represents a promising strategy for synergistic cancer therapy, addressing both primary tumor control and metastatic suppression.