Abstract
Background/Objectives: 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 (H(2)O(2)) levels and the activation of protective autophagy in response to oxidative stress. Methods: To overcome these obstacles, we developed a tumor microenvironment-responsive, pancreatic cancer-targeted CDT nanoamplifier-H-MnO(2)/GOX&CQ-iRGD-comprising a hollow mesoporous MnO(2) 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 H(2)O(2), enhancing Fenton-like reactions. CQ suppresses autophagy induced by oxidative stress, thereby alleviating therapy resistance. The iRGD peptide targets integrin α(v)β(3), which is overexpressed on pancreatic cancer cells and tumor vasculature, promoting deep tumor penetration and enhanced delivery efficiency. Results: We comprehensively characterized the nanoplatform's physicochemical properties, tumor microenvironment triggered degradation, controlled drug release, glucose-driven H(2)O(2) generation, and hydroxyl radical production in vitro. Cellular studies assessed nanoparticle uptake, intracellular H(2)O(2) production, autophagy inhibition, and cytotoxicity. In vivo experiments further demonstrated effective tumor targeting and significant therapeutic outcomes in pancreatic cancer models. Conclusions: This nanoplatform addresses major barriers of CDT-namely, insufficient H(2)O(2) levels, autophagy-mediated resistance, and limited intratumoral penetration-offering a promising strategy for pancreatic cancer treatment.