Design of manganese ion coated Prussian blue nanocarrier for the therapy of refractory diffuse large B-cell lymphoma based on a comprehensive analysis of ferroptosis regulators from clinical cases

Diffuse large B-cell lymphoma (DLBCL) is a prevalent human malignancy, and understanding its biology will help identify problems in refractory patients and customize alternative therapies for them. We found that DLBCL can be stratified into two independent subtypes with different clinical characteristics and outcomes by consensus clustering of expression of ferroptosis regulatory genes, which proves that ferroptosis is effective in treating refractory cases. In this work, we constructed a novel ferroptosis nanocarrier (PBPMn@PEG) by coating Prussian blue nanoparticles with manganese ions and encapsulating them with poly(ethyleneglycol). The low efficiency of the Fenton reaction of Prussian blue nanoparticles can be improved greatly by manganese coating, and can effectively generate hydroxyl radicals, and induce ferroptosis of lymphoma cells (SU-DHL-10 cells) by down-regulating ferroptosis suppressor genes and up-regulating ferroptosis driver genes. It also induces effective cell apoptosis, which is synergistic with ferroptosis for DLBCL therapy. In vivo experiments also prove that PBPMn@PEG achieved a better anti-tumor effect by up-regulating COX2, HO-1/hemeoxygenase-1 (HMOX1), and NADPH oxidase-4 (NOX4), and down-regulating FSP1 and GPX4, with lower biotoxicity. As a novel and potential DLBCL drug carrier, our discovery served as a foundation for the treatment of the refractory DLBCL by inducing ferroptosis for DLBCL treatment in addition to the therapeutic effect of drugs.