Nanozyme-mediated delivery of natural compounds induces ferroptosis to potentiate radiotherapy in bladder cancer

Immune suppression within the tumor microenvironment (TME) is a major obstacle to effectively treating bladder cancer; however, inducing immunogenic cell death via ferroptosis has attracted increasing attention as a means to boost antitumor immunity. A ruthenium (Ru)-incorporated ZIF-8-based nanostructure loaded with the ferroptosis inducer baicalin (BA) and coated with a hyaluronic acid (HA) shell is described as a radioimmunotherapeutic platform for bladder cancer treatment. Incorporation of Ru, a high-atomic-number element, significantly increased local radiation energy deposition, thus improving radiotherapeutic outcomes at tumor sites. The synthesized nanozyme showed intracellular catalase-like activity, promoting oxygen production to suppress hypoxia and reduce radioresistance within the TME. Peroxidase-mimicking activity showed efficient generation of reactive oxygen species (ROS). HA functionalization demonstrated selective tumor homing by targeting the CD44 receptor, which is overexpressed in bladder cancer, enabling effective drug delivery to malignant tissue. BA was released in situ, reprogramming the immunosuppressive TME. When combined with ionizing radiation, this approach elicited a potent systemic immune response, effectively inhibiting primary tumor progression and metastasis. This strategy addresses immune suppression and provides a viable synergistic therapeutic approach for bladder cancer treatment.