Covalent Organic Framework Bispecific Nanosystem for the Combined Treatment of Acute Myeloid Leukemia.

Drug resistance remains a significant challenge in the clinical treatment of acute myeloid leukemia (AML). Therefore, there is an urgent need to develop a novel combinatorial therapy strategy, aiming to overcome drug resistance and improve therapeutic outcomes in AML. Herein, we developed a covalent organic framework bispecific nanosystem, namely glucose oxidase-loaded iron porphyrin covalent organic framework coated with bone marrow stromal cell membrane and functionalized with anti-CD3 and anti-PD-L1 antibodies (abbreviated FeC-G@M-C&P). The fabricated FeC-G@M-C&P displayed good cascade catalytic activity. The bone marrow stromal cell membrane endowed the nanosystem with robust targeting ability, which further triggered abundant reactive oxygen species (ROS) production for chemodynamic therapy. Moreover, bone marrow stromal cell membrane component suppressed the migration and adhesion of C1498 cells by interfering with the CXCR4/CXCL12 axis. Meanwhile, anti-CD3 and anti-PD-L1 antibodies improved T cell activation, relieved immune suppression, and jointly enhanced T cell-mediated immune responses against leukemia cells. Experimental results indicated that the FeC-G@M-C&P plus T cells group showed better anti-leukemia effects compared with other groups, which can be attributed to the integration of chemodynamic therapy, CXCR4/CXCL12 axis blockade therapy and immunotherapy. Collectively, the fabricated nanosystem provided a promising approach for the combined treatment of AML.