Enhanced Biohomogeneous Composite Membrane-Encapsulated Nanoplatform with Podocyte Targeting for Precise and Safe Treatment of Diabetic Nephropathy

Diabetic nephropathy (DN), associated with high mobility and disability, is the leading cause of end-stage kidney disease worldwide. Dysfunction of the mammalian target of the rapamycin (mTOR) pathway and reactive oxygen species (ROS) activation in the glomeruli is the main hypnosis for DN progression. However, the use of mTOR inhibitors for DN treatment remains controversial. In this study, we built a multifunctional selective mechanistic target of rapamycin complex 1 (mTORC1) inhibiting nanoplatform (naming as ESC-HCM-B) that targets the release of mTOR and ROS inhibitors near podocytes, aiming to confirm whether combination therapy is an alternative method for DN treatment. The results showed that ESC-HCM-B achieved high drug loading because of the core mesoporous silica nanoparticles (MSNPs), and the enhanced biohomogeneous composite membrane endowed ESC-HCM-B with the characteristics of avoiding immune phagocytosis, automatic valve-type slow-release drug, and high stability. In vitro, the nanoplatform showed high efficiency in podocyte targeting but no significant cytotoxicity or apoptotic promotion. In particular, the quantum dots carried by ESC-HCM-B further amplified the effect of "nanoenzyme"; this mechanism reduced the ROS level in podocytes induced by high glucose, protected mitochondrial damage, and restored mitochondrial energy metabolism. In vivo, the nanoplatform specifically targeted the glomerular and podocyte regions of the kidney. After treatment, the nanoplatform significantly reduced urinary protein levels and delayed glomerulosclerosis in DN rats. This nanoplatform provides a safe and effective strategy for DN treatment.