Photodynamic therapy (PDT) holds significant promise for treating pancreatic cancer by utilizing photosensitizers to generate reactive oxygen species (ROS) that induce tumor cell death. However, the therapeutic efficacy of PDT is hindered by inadequate ROS accumulation. Herein, we develop a DNA nanoflower that enables the controlled codelivery of Cas9 ribonucleoprotein (RNP), hemin, and chlorin e6 for synergistic PDT. The Cas9 RNP selectively knocks out the antioxidant regulator nuclear factor E2-related factor 2 (Nrf2), thereby increasing cancer cells'' sensitivity to ROS. Simultaneously, the G-quadruplex/hemin complex catalyzes the conversion of endogenous H2O2 into O2, alleviating tumor hypoxia and supplying additional oxygen for PDT. This synergistic approach substantially amplifies ROS accumulation by attenuating ROS elimination and enhancing ROS generation, demonstrating high gene editing efficiency, significant Nrf2 down-regulation, elevated apoptosis, and remarkable antitumor efficacy in pancreatic cancer cells and a mouse model, underscoring the potential for precision medicine.
[1]Fudan Univ, Dept Chem, State Key Lab Mol Engn Polymers, Shanghai 200438, Peoples R China.
[2]Tianjin Univ, Sch Synthet Biol & Biomfg, Key Lab Syst Bioengn MOE, State Key Lab Synthet Biol,Frontiers Sci Ctr Synth, Tianjin 300350, Peoples R China.
[3]Tianjin Med Univ, Dept Breast Oncol, Canc Inst & Hosp, Tianjin 300350, Peoples R China.
[4]Tianjins Clin Res Ctr Canc, Tianjin 300350, Peoples R China.
[5]Tianjin Med Univ, Key Lab Breast Canc Prevent & Therapy, Tianjin 300350, Peoples R China.
(8.0+极速模式)