Engineered Photoactivatable Nanomicelles for Ferroptosis-like Combinational Tumor Therapy In Vitro and In Vivo

Nitric oxide (NO)-based gas therapy has attracted increasing attention as a promising approach for tumor treatment, but elevated levels of glutathione (GSH) in the tumor microenvironment significantly limit their therapeutic effectiveness. In this study, a type of engineered photoactivatable nanomicelles Ce6/NI@PEP@HA (CNPH) were developed for combinational photodynamic and NO gas therapy. CNPH was capable of targeted accumulation to tumors, where it depleted GSH and released NO to effectively produce reactive oxygen species (ROS) with oxidative damage under laser irradiation at 660 nm. The GSH consumption induced the deactivation of glutathione peroxidase activity, leading to enhanced accumulation of toxic lipid peroxide and enabled a ferroptosis-like therapeutic outcome. Additionally, the effective production of NO and ROS resulted in mitochondrial dysfunction, characterized by the disruption of mitochondrial membrane potential and decreased adenosine triphosphate concentration. The in vivo animal experiments indicated that the combinational photodynamic and NO gas therapy achieved a tumor inhibition of 89.1%, and it has proven to be a more effective tumor therapy strategy in contrast to any single modality. In consequence, ferroptosis-like combinational tumor therapy has opened up a new horizon to a cutting-edge and noninvasive paradigm for advanced tumor treatments.