Enzyme-responsive liposomes target endoplasmic reticulum stress-mediated apoptosis for rheumatoid arthritis therapy

IF 8.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-09-23 DOI:10.1016/j.phymed.2025.157299

Chenglong Li , Can Qian , Jie Zhang , Ya Huang , Xiaolin Zhao , Huaiyu Su , Yingying Hou , Chen Li

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引用次数: 0

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

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酶反应性脂质体靶向内质网应激介导的细胞凋亡用于类风湿关节炎治疗

背景类风湿性关节炎（RA）是一种慢性自身免疫性疾病，其特征是持续的滑膜炎症和关节破坏。纤维母细胞样滑膜细胞（FLSs）凋亡不足通过促进增生和炎性细胞因子的分泌而显著参与RA的发病。雷公藤红素（Celastrol， CLT）是一种从雷公藤中提取的五环三萜，已显示出通过内质网（ER）应激介导途径诱导细胞凋亡的前景。但其溶解度差、脱靶效应等限制了其临床应用。CLT靶向治疗FLSs及其内质网可提高治疗效果，同时降低毒性。方法我们设计了负载clt的酶反应脂质体（CLT-FELipos），脂质体由透明质酸（HA）、寡肽GPA（用于在fls上识别FAP-α）、er靶向KDEL肽和可切割的PEG链功能化。在体外，我们评估了CLT-FELipos对fls的特异性摄取（通过FAP-α/GPA和CD44/HA相互作用）、内质网积累和细胞凋亡诱导。在体内，佐剂诱导的关节炎（AIA）大鼠用各种配方治疗。使用近红外成像评估关节分布，通过测量足跖肿胀、组织学分析和骨侵蚀的显微ct来评估治疗效果。结果clt - felipos与FLSs上的FAP-α选择性结合，随后发生PEG裂解和cd44介导的细胞摄取。共聚焦显微镜证实内质网内有特异性堆积。在AIA大鼠中，CLT-FELipos具有关节特异性分布，可有效降低关节炎关节的FLS数量。CLT-FELipos治疗带来炎症缓解，骨侵蚀修复和最小的不良反应。值得注意的是，从稳定的体重和正常的肝肾功能测试结果可以看出，CLT-FELipos引起的全身毒性很小。结论CLT- felipos是一种特异性靶向FLS和ER的新型药物传递系统，可通过诱导增殖性FLS细胞凋亡来提高CLT治疗RA的指标。双靶向策略（FAP-α/CD44用于FLSs和KDEL用于ER）确保精确的药物递送，同时减少炎症和关节破坏，提高安全性。这种创新的方法具有治疗类风湿性关节炎的潜力，值得进一步的临床研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.