Prussian-Blue-Functionalized Polypyrrole Nanozyme via PTEN Activation and Hypoxia Reversal for Enhanced Photothermal Therapy of Tumor

Photothermal therapy (PTT) faces critical limitations due to tumor hypoxia, intrinsic resistance, and metastasis. To address these challenges, we developed a trimodal nanoplatform (R-R/PB@PPy NEs) by synergizing Prussian blue (PB)/polypyrrole (PPy) nanozymes, tumor suppressor reactivation, and immune modulation. Through Fe 3+ -mediated one-step oxidative polymerization, PB and PPy were integrated into a hybrid nanozyme and further functionalized with rosiglitazone (PPAR-γ agonist) and rutin (tumor-targeting ligand). The R-R/PB@PPy NEs achieved a photothermal conversion efficiency of 31.6% and catalase/superoxide dismutase-like enzymatic activity, persistently alleviating hypoxia via oxygen generation. Simultaneously, AKT/mTOR-mediated PTEN upregulation suppressed tumor proliferation and metastasis. Rutin-mediated tumor targeting enhanced drug accumulation at tumor sites, which synergistically amplified immunogenic cell death induction, promoting dendritic cell maturation and cytotoxic T-cell infiltration. In vivo, this platform completely inhibited 4T1 tumor growth, eradicated lung metastasis, and prevented recurrence (0% at 56 days) with an 80% long-term survival rate and no systemic toxicity. By unifying catalytic nanozyme design, PTEN-driven sensitization, and immune activation, this study establishes an interdisciplinary strategy to overcome resistance in PTT, offering a translatable approach for precision cancer therapy through tumor microenvironment modulation.