Glomerulonephritis (GN), a major cause of chronic kidney disease, remains difficult to treat due to inefficient glomerular drug delivery following systemic administration. Here, we report a targeted nanotherapeutic strategy based on celastrol (CLT)-loaded, positively charged poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CLT@R8-PLNs) designed to promote glomerular accumulation. To further improve renal targeting, a reticuloendothelial system (RES) blockade strategy was employed by pre-saturating phagocytic organs with blank nanoparticles prior to CLT@R8-PLNs administration. In vivo biodistribution studies demonstrated that RES blockade markedly reduced hepatic and splenic sequestration while significantly enhanced glomerular accumulation of the nanoparticles. In a rat model of mesangioproliferative glomerulonephritis (MsPGN), this delivery strategy effectively alleviated glomerular inflammation and suppressed mesangial cell proliferation, accompanied by pronounced downregulation of monocyte chemoattractant protein-1, intercellular adhesion molecule-1, interleukin-6, interleukin-1β, and proliferating cell nuclear antigen. Collectively, these results demonstrate that integrating RES blockade with size-dependent passive targeting and charge-mediated glomerular interactions enables enhanced glomerular delivery and therapeutic efficacy, providing a rational nanomedicine-based approach for the treatment of GN.