Self-Adaptive Nanocarriers\nOvercome Multiple Physiological\nBarriers to Boosting Chemotherapy of Orthotopic Pancreatic Cancer

Chemotherapy is the primary treatment option for pancreatic\ncancer,\nalthough nanocarrier-based drug delivery systems often struggle with\nmultiple physiological barriers, limiting their therapeutic efficacy.\nHere, we developed a pH/reactive oxygen species (ROS) dual-sensitive\nself-adaptive nanocarrier (DAT<sub>CPT</sub>) encapsulating camptothecin\n(CPT), an analog of the pancreatic chemotherapeutic drug irinotecan\n(CPT-11), to enhance chemotherapy outcomes in orthotopic pancreatic\ncancer by addressing multiple physiological barriers. The nanocarrier\nfeatures a peripherally positively charged arginine (Arg) residue\non DAT<sub>CPT</sub> and is masked with an acid-labile 2,3-dimethylmaleic\nanhydride (DA) to improve circulation time. In the acidic tumor microenvironment\n(TME), DA dissociates, exposing arginine to facilitate nanocarrier\nbinding and internalization of DAT<sub>CPT</sub>. Subsequently, peroxynitrite\n(ONOO<sup>–</sup>) is generated by a cascade reaction between\nexposed Arg and ROS, which effectively activates matrix metalloproteinases\n(MMPs) to degrade the dense extracellular matrix (ECM) and enhance\nthe deep accumulation and penetration of DAT<sub>CPT</sub>. Meanwhile,\nONOO<sup>–</sup> inhibits tumor metastasis by influencing mitochondrial\nfunction, preventing adenosine triphosphate (ATP) production, and\ninhibiting ATP-dependent tumor-derived microvesicles (TMVs). This\nstudy presents a promising strategy to develop efficient nanocarriers\nto address multiple physiological barriers in antipancreatic cancer\ntherapy.