Renal fibrosis often occurs in chronic kidney disease, and effective treatment is needed. Celastrol (CEL) may attenuate renal fibrosis, but it distributes throughout the body, leading to severe systemic toxicities. Here we designed a system to deliver CEL specifically to interstitial myofibroblasts, which is a key driver of renal fibrogenesis. Fibronectin is highly expressed in fibrotic kidney. The pentapeptide CREKA, which specifically binds fibronectin, was conjugated to PEGylated liposomes (CREKA-Lip). CREKA-coupled liposomes significantly increased the uptake of unmodified liposomes by activated NRK-49F renal fibroblasts. Systemic administration of CREKA-Lip to mice led to their accumulation in fibrotic kidney, where they were specifically internalized by interstitial myofibroblasts. Loading CEL into CREKA-Lip effectively inhibited the activation and proliferation of NRK-49F cells in vitro, and they markedly alleviated renal fibrosis, injury and inflammation induced by unilateral ureteral obstruction in mice. Besides, CEL-loaded CREKA-Lip was associated with significantly lower toxicity to major organs than free CEL. These results suggest that encapsulating CEL in CREKA-Lip can increase its therapeutic efficacy and reduce its systemic toxicity as a potential treatment for renal fibrosis.