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

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.