Chondroitin Sulfate-Based ROS-Responsive Nanoparticles Targeting Activated Myofibroblasts via CD44 Receptors for the Renal Fibrosis Therapy

Renal fibrosis, a central pathological feature in chronic kidney disease progression, is marked by aberrant myofibroblast activation and excessive extracellular matrix deposition. Currently, no effective therapies are available to reverse this condition. Although celastrol (CEL) exhibits potent antifibrotic activity, its clinical application is hindered by poor solubility and significant systemic toxicity. To overcome these limitations, we developed a CD44-targeted and reactive oxygen species (ROS)-responsive nanoparticle (CEL@CB) for targeted renal delivery. The nanoparticle was constructed by conjugating bilirubin (BR) to chondroitin sulfate (CS), creating an amphiphilic CS-BR conjugate that self-assembles into nanoparticles capable of encapsulating CEL. The CS shell enables active targeting of CD44 receptors, which are highly overexpressed on activated renal myofibroblasts, while the BR core responds to elevated ROS levels in fibrotic kidneys, triggering drug release and simultaneously scavenging ROS to alleviate inflammation. Both <i>in vitro</i> and <i>in vivo</i> studies demonstrated that CEL@CB nanoparticles facilitate targeted CEL delivery to activated myofibroblasts, achieving a drug accumulation in fibrotic kidneys more than 2-fold higher than in healthy controls. Treatment with CEL@CB reduced the expression of key fibrotic markers (α-SMA and Col1a1) by approximately 30-70% at both mRNA and protein levels and decreased serum creatinine and blood urea nitrogen (BUN) levels by about 50%, thereby significantly attenuating folic acid-induced renal fibrosis, restoring renal function, and mitigating histological damage. Importantly, this targeted strategy markedly minimized the toxicity to the heart, testis, and hematological systems associated with free CEL. This dual-functional nanoparticle combines CD44-mediated renal targeted delivery with ROS-responsive drug release, offering a novel approach for antifibrotic therapy.