Treating diabetic sepsis (DS) can be challenging due to the persistent infection of multiple organs. To address this complicated pathological condition, it is necessary to develop advanced materials and gain a better understanding of their roles. In this study, we developed a two-dimensional planar material with a rectangular DNA origami nanostructure (termed Rec-DON). Rec-DON was used to improve liver and renal function in mice with DS due to its preferential accumulation in the kidney and liver and its superior anti-inflammatory and reactive oxygen species (ROS) scavenging activities. The role of Rec-DON in the treatment of DS in mice was investigated using quantitative proteomics. The study found that Rec-DON can regulate key proteins primarily located in the cytoplasm and mitochondrion, involved in protein transport, antigen processing and presentation, and steroid metabolic process, and performed various proteins binding to restore liver and renal function in DS mice. The study presented Rec-DON as a liver and kidney targeting material and revealed its role in alleviating multi-organ injury in DS.