Stem Cell Membrane Biomimetic Nano‐Formulation Achieves the Delivery of MKP5 to Ameliorate Diabetic Kidney Disease via the P38 and ERK Pathway

ABSTRACT Diabetic kidney disease (DKD) is a complication of diabetes that frequently progresses to end‐stage renal disease, posing a significant threat to patients' lives. Due to the complex microenvironment associated with DKD, current treatment and reversal strategies remain inadequate. While the protective role of mitogen‐activated protein kinase phosphatase 5 (MKP5) in diabetes has been established, its specific function in DKD remains unclear. This study aims to investigate the role and underlying mechanism of MKP5 in DKD and propose a novel therapeutic target for its treatment. We found that MKP5 expression was reduced in the renal glomeruli of streptozotocin‐induced DKD mice. MKP5‐knockout mice exhibited more pronounced progression of DKD. The regulatory mechanism of MKP5 primarily involved modulation of the extracellular signal‐regulated kinase (ERK) and P38 pathways in glomerular mesangial cells and podocytes, respectively. Consequently, polylactic acid‐glycolic acid copolymer (PLGA) particles were employed to carry the MKP5 plasmid, with mesenchymal stem cell membrane (MSCM, M) serving as the external encapsulating structure, resulting in the fabrication of a nano‐formulation designated MKP5@NP‐M. This formulation inhibited the secretion of inflammatory factors in the glomerulus, prevented collagen deposition and mesangial expansion, thereby inhibiting the progression of DKD. These findings uncover the potential anti‐inflammatory regulatory function of MKP5 in the glomerulus and provide a combined strategy for treating DKD.