Nephrotic syndrome (NS) is one of the most common pediatric kidney diseases characterized by massive proteinuria and generalized edema that accounts for considerable mortality. Although the etiology of NS is not yet fully understood, altered mitochondrial metabolism, higher levels of oxidative stress, and chronic inflammation are considered the main causes of NS. Thus, reducing the level of reactive oxygen species (ROS) and inhibiting inflammation may effectively improve NS. In this study, the small molecule compound ruxolitinib phosphate salt (RP) was identified and we found it could improve NS by inhibiting cellular inflammation and reducing ROS production to exert a cytoprotective effect, but it also had some side effects. A novel two-dimensional material, black phosphorus nanosheets (BPNSs), was used to efficiently load RP and proximal tubule cells (PTCs) targeting peptide G3-C12 through electrostatic interaction. The mod-ification of G3-C12 promoted cellular uptake of BPNSs, and the endocytosis of BPNSs@G3-C12 was primarily via micropinocytosis. RP@BPNSs@G3-C12 actively targeted PTCs and released RP in a pH-responsive manner in the acidic microenvironment of inflammation. It inhibited LPS-triggered activation of the NF-Kappa B and JNK signaling pathways in RAW264.7 cells, and reduced the production of inflammatory factors such as NO, TNF-alpha, and IL-6. RP@BPNSs@G3-C12 further exhibited cytoprotective effect against doxorubicin damage, oxidative stress and apoptosis. The anti-apoptotic effect may be mainly through the Caspase 3 signaling pathway. Moreover, RP@BPNSs@G3-C12 treatment could also reduce renal inflammation, improve renal injury, apoptosis and oxidative stress in vivo, thereby improve renal functions of NS patients.(c) 2022 Elsevier Ltd. All rights reserved.