Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and joint destruction. Insufficient apoptosis of fibroblast-like synoviocytes (FLSs) significantly contributes to the pathogenesis of RA by promoting hyperplasia and inflammatory cytokine secretion. Celastrol (CLT), a pentacyclic triterpene derived from Tripterygium wilfordii, has shown promise in inducing apoptosis via endoplasmic reticulum (ER) stress-mediated pathways. However, its clinical application is limited by poor solubility and off-target effects. Targeted delivery of CLT to FLSs and their ER could enhance therapeutic efficacy while minimizing toxicity.We engineered CLT-loaded, enzyme-responsive liposomes (CLT-FELipos) functionalized with hyaluronic acid (HA), oligopeptide GPA (for FAP-α recognition on FLSs), an ER-targeting KDEL peptide, and cleavable PEG chains. In vitro, CLT-FELipos were evaluated for FLS-specific uptake (via FAP-α/GPA and CD44/HA interactions), ER accumulation, and apoptosis induction. In vivo, adjuvant-induced arthritis (AIA) rats were treated with various formulations. Joint distribution was assessed using near-infrared imaging, and therapeutic efficacy was evaluated through measurements of paw swelling, histological analysis, and micro-CT for bone erosion.CLT-FELipos demonstrated selective binding to FAP-α on FLSs, followed by PEG cleavage and CD44-mediated cellular uptake. Confocal microscopy confirmed specific accumulation within the ER. In AIA rats, CLT-FELipos showed joint-specific distribution and effectively reduced FLS numbers in arthritic joints. Treatment with CLT-FELipos brought about inflammatory remission, bone erosion repair, and minimal adverse effects. Notably, CLT-FELipos caused minimal systemic toxicity, as evidenced by stable body weight and normal liver and kidney function tests results.CLT-FELipos represents a novel drug delivery system that specifically targets FLS and ER, which enhances CLT's therapeutic index in RA by inducing apoptosis in hyperplastic FLSs. The dual-targeting strategy (FAP-α/CD44 for FLSs and KDEL for ER) ensures precise drug delivery while reducing inflammation and joint destruction with improved safety. This innovative approach holds potential for RA treatment and warrants further clinical investigation.Copyright © 2025. Published by Elsevier GmbH.