Tumor-homing cerium nanozyme platform enables coordinated drug release and STING activation for bladder cancer treatment

Abstract Non-muscle-invasive bladder cancer (NMIBC) carries 70% incidence yet remains plagued by high recurrence because single-modality chemotherapy or immunotherapy is crippled by rapid urinary clearance, poor tumor specificity, and narrow therapeutic windows. To overcome these challenges, we develop a homologous-targeted cerium nanozyme (HMZCO/DS@CM) that co-loads doxorubicin and the STING agonist MSA-2 in Mn/Zr-co-doped CeO₂ cores camouflaged with tumor-cell membranes. We discover that Mn/Zr substitution accelerates Ce³⁺/Ce⁴⁺ redox cycling, sustaining peroxidase- and SOD-like activities to deplete glutathione and amplify reactive oxygen species, thereby synchronizing immunogenic cell death with STING activation. The tumor cell membrane coating prolongs circulation, evades immune recognition, and directs NMIBC-homing, enabling pH-responsive, spatially and temporally controlled delivery co-release of both drugs within tumors. In orthotopic NMIBC models, HMZCO/DS@CM achieves five-fold tumor enrichment versus monotherapy, unleashes potent systemic immunity, blocks recurrence and metastasis with negligible toxicity. Collectively, this catalytic nanozyme–membrane nanoplatform transforms intravesical instillation into a sustained-release chemo-immunotherapy depot, reactivating local antitumor immunity and reducing NMIBC recurrence, thereby offering a practical adjuvant strategy with minimal systemic impact. Graphical Abstract