A Smart DNA Nanoframework Enables Synergistic Photodynamic Therapy of Pancreatic Cancer

Abstract Photodynamic therapy (PDT) holds great promise for treating pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancers, but its clinical application is hindered by limited generation and accumulation of reactive oxygen species (ROS) due to tumor hypoxia and the organism's antioxidant defense mechanisms. To address this challenge, a smart DNA nanoframework capable of controlled co‐delivery of Cas9 ribonucleoprotein (RNP), hemin, and chlorin e6 (Ce6) to enable synergistic PDT for PDAC is developed. This nanoframework employs a hybridization chain reaction and phase transition to achieve high payload loading capacity while overcoming steric hindrance. The G‐quadruplex/hemin complex mimics horseradish peroxidase activity to convert endogenous H 2 O 2 to O 2 , alleviating tumor hypoxia. Additionally, Cas9 RNP targets the nuclear factor E2‐related factor 2 (Nrf2) pathway, downregulating Nrf2 expression and diminishing the antioxidant response, thereby enhancing ROS accumulation. The synergistic effect of O₂ generation and Nrf2 suppression significantly enhances ROS‐induced apoptosis in PDAC cells. In vitro, the system demonstrates efficient gene editing and robust downregulation of Nrf2, while in vivo studies in a PDAC mouse model reveal remarkable antitumor efficacy. This smart DNA nanoframework represents a promising strategy for enhancing PDT through precise genetic and biochemical modulation.