Diabetic kidney disease (DKD) represents a major diabetes-related complication and is among the most important causes of end-stage renal disease (ESRD). Current therapies mainly focus on glycemic control but seldom reverse established renal injury. Berberine (BBR) shows promise for DKD through glucose-lowering, anti-inflammatory, and antioxidant effects, yet its translation is limited by poor bioavailability and rapid metabolism. Here, we developed ZIF-BBR-BPNs, a nanoparticle system that encapsulates BBR in a zeolitic imidazolate framework (ZIF) core and applies an epigallocatechin gallate (EGCG) coating to improve stability, systemic exposure, and renal enrichment. In vitro, ZIF-BBR-BPNs decreased oxidative stress, inflammatory activation, and apoptosis, helping maintain glomerular endothelial cell integrity and function. In vivo, the formulation reduced albuminuria and improved renal inflammation, fibrosis, and glomerular damage, with stronger effects than free BBR or metformin. Notably, the formulation increased systemic exposure and enabled passive renal accumulation, supporting sustained therapeutic activity at injury sites. Overall, this multi-target strategy against metabolic stress, oxidative injury, inflammation, and fibrosis enhances BBR efficacy and supports ZIF-BBR-BPNs as a promising candidate for DKD therapy.