Pancreatic Cancer-Targeting Cascade Nanoamplifier Enables Self-Replenishing H2O2 Generation and Autophagy Disruption in Chemodynamic Therapy

<b>Background/Objectives:</b> Conventional therapeutic strategies exhibit limited efficacy against pancreatic cancer, primarily due to its profoundly hypoxic tumor microenvironment and dense fibrotic stroma. Chemodynamic therapy (CDT) holds promise; however, its application in pancreatic cancer is restricted by insufficient endogenous hydrogen peroxide (H₂O₂) levels and the activation of protective autophagy in response to oxidative stress. <b>Methods:</b> To overcome these obstacles, we developed a tumor microenvironment-responsive, pancreatic cancer-targeted CDT nanoamplifier-H-MnO₂/GOX&CQ-iRGD-comprising a hollow mesoporous MnO₂ shell co-loaded with glucose oxidase (GOX) and chloroquine (CQ), and surface-functionalized with the tumor-penetrating peptide iRGD. GOX catalyzes glucose oxidation to generate H₂O₂, enhancing Fenton-like reactions. CQ suppresses autophagy induced by oxidative stress, thereby alleviating therapy resistance. The iRGD peptide targets integrin α_vβ₃, which is overexpressed on pancreatic cancer cells and tumor vasculature, promoting deep tumor penetration and enhanced delivery efficiency. <b>Results:</b> We comprehensively characterized the nanoplatform's physicochemical properties, tumor microenvironment triggered degradation, controlled drug release, glucose-driven H₂O₂ generation, and hydroxyl radical production in vitro. Cellular studies assessed nanoparticle uptake, intracellular H₂O₂ production, autophagy inhibition, and cytotoxicity. In vivo experiments further demonstrated effective tumor targeting and significant therapeutic outcomes in pancreatic cancer models. <b>Conclusions:</b> This nanoplatform addresses major barriers of CDT-namely, insufficient H₂O₂ levels, autophagy-mediated resistance, and limited intratumoral penetration-offering a promising strategy for pancreatic cancer treatment.