Multi-responsive cascade enzyme-like catalytic nanoassembly for ferroptosis amplification and nanozyme-assisted mild photothermal therapy.

Ferroptosis is greatly restricted by low reactive oxygen species (ROS) generation efficiency, and the inherent self-protection mechanism originating in heat shock proteins (HSPs) seriously impedes the efficiency of photothermal therapy (PTT). Herein, we designed an intelligent strategy utilizing cascade catalytic nanoassemblies (Au@COF@MnO) with triple-enzyme activity for amplifying ferroptosis therapy and improving the efficiency of PTT in tumor. Gold nanozyme was encapsulated within a hollow manganese dioxide (MnO) shell with the help of covalent organic frameworks (COFs). The nanoassemblies possess the ability of photothermal conversion. Mechanism studies suggested that glutathione (GSH) depletion by Au@COF@MnO leads to the inactivation of glutathione peroxidase 4 (GPX4). This effect synergized with Mn-mediated reactive oxygen species (ROS) generation to enhance the accumulation of lipid peroxide (LPO), thereby inducing high-efficiency ferroptosis. Notably, gold nanozyme facilitated the conversion of glucose into gluconic acid and hydrogen peroxide (HO). This process augmented the endogenous HO levels necessary for Fenton chemistry, which could effectively promote the generation of ROS. Simultaneously, glucose depletion downregulated the expression of HSPs induced by hyperthermia, consequently reducing cellular heat resistance for enhancing PTT. Therefore, the cascade catalytic nanoassembly not only exhibits high tumor inhibition and admirable biosafety, but also possesses trimodal imaging performance for imaging-guided tumor therapy in vivo, holding great potential for clinical application. STATEMENT OF SIGNIFICANCE: This study engineered multi-responsive cascade catalytic nanoassembly (Au@COF@MnO) with triple enzymatic functions for amplifying ferroptosis therapy and improving the efficiency of PTT in tumor. The nanoassembly exhibited multi-responsive release and great photothermal conversion performance. Glucose consumption-evoked starvation downregulated the hyperthermia-induced expression of HSPs in tumor cells, thereby improving the efficacy of PTT. Mechanism studies suggested that GSH depletion by Au@COF@MnO lead to the inactivation of GPX4, which synergized with Mn-mediated ROS generation to bolster the accumulation of LPO, thereby inducing high-efficiency ferroptosis. Moreover, the nanoassembly demonstrated trimodal (PT, PA, and MR) imaging in vivo, enabling the visualization of the tumor treatment with nanoassembly. Such nanoassembly exhibited high tumor inhibition and admirable biosafety in tumor therapy in vivo, holding a great potential for clinical application.