Abstract

Bladder cancer treatment is challenged by tissue damage, inflammation, and resistance to mild hyperthermia. Magnetic hyperthermia therapy offers a promising solution, but issues such as rapid nanoparticle clearance and limited tumor retention still hinder its effectiveness. Here, we report a mild magnetic hyperthermia strategy that integrates pH-responsive magnetic ferritin with a glutathione-activated nitric oxide donor to sensitize tumors while minimizing off-target damage. Under an alternating magnetic field, ferritin-confined Fe3O4 cores generate subablative heat through relaxation losses, while the ferritin shell ensures biocompatibility, enhances tumor uptake, and captures cyanoferrate byproducts to mitigate side effects. Combined with nitric oxide gas therapy, this regimen weakens tumor thermotolerance, reverses the immunosuppressive tumor microenvironment, induces an abscopal effect, and dampens NF-κB-mediated inflammatory signaling. By integrating tumor targeting, alleviation of immunosuppression, and inflammation control, this approach achieves greater tumor regression and better systemic tolerability than monotherapy, thereby advancing hyperthermia therapy.