An oral nanocombinatorial agent exhibits pleiotropic improvement in diabetic nephropathy via modulation of the SCAP/SREBPs pathway

Abstract The multifaceted pathogenesis and multi-cellular involvement of diabetic nephropathy (DN) stand in stark contrast to the inadequacy of conventional single-target therapeutic strategies. This disparity underscores the urgent need for novel drugs with comprehensive targeting capabilities. Herein, the SREBP cleavage-activating protein/sterol regulatory element-binding proteins (SCAP/SREBPs) pathway was identified as a central driver in DN, where its activation in key renal parenchymal cells promotes lipid metabolic disorders and inflammation, thereby exacerbating renal injury. Guided by this discovery, we screened a 245-member nanoparticle library comprising SCAP inhibitors self-assembled with chitosan, and identified chitosan-lycorine nanoparticles (CLNPs) as the optimal candidate. Owing to its efficient intestinal absorption and significant accumulation in mesangial and proximal tubular epithelial cells, oral CLNPs strongly alleviated renal injury in a murine model of DN by counteracting lipid accumulation and inflammation, consistent with SCAP/SREBPs pathway inhibition. Critically, CLNPs prevented hepatotoxicity from free lycorine, which reduced mortality and enabled safer prolonged therapy. Together, our findings demonstrate the viability of CLNPs for DN, thereby offering a generalizable strategy for combating complex diseases through a single combinatorial agent that counters multiple co-existing pathological injuries. Graphical Abstract