Chemotherapy is the primary treatment option for pancreatic cancer, although nanocarrier-based drug delivery systems often struggle with multiple physiological barriers, limiting their therapeutic efficacy. Here, we developed a pH/reactive oxygen species (ROS) dual-sensitive self-adaptive nanocarrier (DATCPT) encapsulating camptothecin (CPT), an analog of the pancreatic chemotherapeutic drug irinotecan (CPT-11), to enhance chemotherapy outcomes in orthotopic pancreatic cancer by addressing multiple physiological barriers. The nanocarrier features a peripherally positively charged arginine (Arg) residue on DATCPT and is masked with an acid-labile 2,3-dimethylmaleic anhydride (DA) to improve circulation time. In the acidic tumor microenvironment (TME), DA dissociates, exposing arginine to facilitate nanocarrier binding and internalization of DATCPT. Subsequently, peroxynitrite (ONOO–) is generated by a cascade reaction between exposed Arg and ROS, which effectively activates matrix metalloproteinases (MMPs) to degrade the dense extracellular matrix (ECM) and enhance the deep accumulation and penetration of DATCPT. Meanwhile, ONOO– inhibits tumor metastasis by influencing mitochondrial function, preventing adenosine triphosphate (ATP) production, and inhibiting ATP-dependent tumor-derived microvesicles (TMVs). This study presents a promising strategy to develop efficient nanocarriers to address multiple physiological barriers in antipancreatic cancer therapy.