Activatable nanoflytrap achieves synergistic "Capture-Block-Regulate" therapy of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most refractory malignancies because of its dense stromal barrier and hypoxic microenvironment. Inspired by the Venus flytrap, we engineered an intelligent nanoflytrap (NT) system that performs a coordinated three stage therapeutic strategy of capture, block, and regulate for precise and sequential treatment. In the capture stage, the CGKRK containing tumor homing peptide enables dual recognition of p32 receptors that are overexpressed on tumor vasculature and PDAC cells, ensuring selective accumulation within the tumor microenvironment. The ROS responsive PLGA-TK-PEI copolymer further guarantees confined activation under oxidative stress. During the block stage, ROS triggered disassembly of NT releases the pro apoptotic peptide _D(KLAKLAK)₂, which disrupts mitochondrial membranes, induces apoptosis, and damages tumor vasculature, resembling the rapid closure of a flytrap. In the regulate stage, dihydroartemisinin undergoes Fe²⁺ catalyzed cleavage to generate reactive oxygen species, triggering ferroptosis and mitigating hypoxia induced resistance. Gadolinium integration facilitates MRI guided monitoring. Transcriptomic and metabolomic analyses reveal that NT orchestrates apoptosis and ferroptosis while disturbing lipid metabolism and suppressing angiogenesis through ROS accumulation. This biomimetic capture block regulate strategy effectively overcomes stromal and hypoxic barriers, providing a promising MRI guided theranostic platform for PDAC.