Spatiotemporal Blockade of Autophagy and Macropinocytosis in Pancreatic Cancer via Lysosomal‐Activated Nanoreactors

Abstract Autophagy blockade has emerged as a promising strategy to enhance the antitumor efficacy of pancreatic ductal adenocarcinoma (PDAC). However, autophagy inhibition in PDAC may induce compensatory macropinocytosis to maintain cellular homeostasis by upregulating nuclear factor erythroid 2‐related factor 2 (NRF2). In this study, lysosomal‐activated nanoreactors loaded with the NRF2 inhibitor ML385 (CPZI‐Ms) are developed to spatiotemporally block autophagy and inhibit macropinocytosis. The nanoreactors, which preferentially accumulate in lysosomes, undergo degradation in the acidic lysosomal environment, triggering a Fenton‐like reaction between the released Cu 2 ⁺ ions and H₂O₂ to generate hydroxyl radicals. This results in lysosomal membrane permeabilization, which further leads to not only lysosomal autophagy blockade, but also the leakage of Cu 2 ⁺ and ML385 into the cytoplasm. Cu 2 ⁺ induces extensive oxidative stress throughout the whole cell, while ML385 suppresses compensatory macropinocytosis response activated by autophagy blocking. As a result, the Panc02 cells become a “besieged fortress”, with impaired autophagic clearance and restricted nutrient uptake. In vivo, CPZI‐Ms effectively suppress tumor growth in Panc02‐bearing mice, offering a promising nanoplatform for enhancing cancer cell killing. Taken together, the present work provides an innovative anti‐tumor insight by spatiotemporally blocking autophagic flux and inhibiting compensatory macropinocytosis.