Preparation of reactive oxygen species-responsive chitosan oligosaccharide nanoparticles and their therapeutic effects on diabetic nephropathy.

Diabetic nephropathy (DN) is a severe complication of diabetes, strongly associated with hyperglycemia-induced oxidative stress. In this study, we developed ROS-responsive nanoparticles (PC-E-CAN NPs) based on chitosan oligosaccharides (CS) for dual-drug co-delivery. Chitosan oligosaccharides were functionalized with 3-carboxyphenylboronic acid (PBA), loaded with epigallocatechin gallate (EGCG) and canagliflozin (CAN), and cross-linked via a thioketal (TK) to form ROS-sensitive nanoparticles. The resulting PC-E-CAN NPs exhibited a uniform particle size of 110 ± 1.8 nm, with drug loading efficiencies of 16.6 ± 0.7% for EGCG and 10.1 ± 0.6% for CAN. PC-E-CAN NPs were efficiently internalized by renal tubular epithelial cells (HK-2 cells), significantly reducing intracellular ROS accumulation and suppressing oxidative stress-induced apoptosis. Under high ROS conditions, both drugs were rapidly released in a responsive manner, with ≥70% cumulative release at 48 h. In vivo experiments revealed that PC-E-CAN NPs accumulated in the kidneys, suggesting potential tubular uptake, significantly reducing blood glucose levels in DN mice, improving renal function (urine protein, creatinine, urea nitrogen), and alleviating renal pathological damage and oxidative stress. This strategy integrates three critical features: ROS-responsive drug release, renal accumulation via appropriate particle size, and combined dual-drug therapy, providing a promising precise treatment for DN.