Tumor Microenvironment‐Responsive Nanoreactor Induces Disulfidptosis in Pancreatic Cancer via Metabolic Interference and Redox Catalysis

ABSTRACT Pancreatic cancer exhibits extensive metabolic reprogramming that supports rapid progression and therapeutic resistance, making metabolic vulnerabilities attractive targets for intervention. Here, a tumor microenvironment‐responsive nanoreactor (Pht@HMnO ₂ ‐HA) is designed to induce disulfidptosis in pancreatic cancer through coordinated metabolic interference and redox catalysis. Following CD44‐mediated tumor targeting and cellular internalization, the nanoreactor's responsive self‐optimization within the tumor microenvironment enables localized release of phloretin, suppressing glucose uptake and pentose phosphate pathway activity and thereby limiting intracellular reducing‐power generation. In parallel, the nanoreactor consumes intracellular glutathione and amplifies oxidative stress via MnO ₂ ‐mediated redox reactions, thereby depleting antioxidant defenses. Together, these processes impose reducing‐power deprivation and disrupt redox homeostasis, leading to cystine accumulation, disulfide stress, actin cytoskeleton collapse, and disulfidptosis in pancreatic cancer cells. Moreover, degradation‐associated Mn ^{2 +} release provides activatable T1‐weighted MRI contrast, enabling noninvasive visualization of intratumoral nanoreactor activation and therapeutic progression. Collectively, this work establishes a theranostic nanoreactor that exploits coupled metabolic and redox vulnerabilities to induce disulfidptosis, offering a mechanistically grounded strategy for precision therapy in pancreatic cancer.