Qi Weizhong, Jin Li, Wu Cuixi, Liao Hao, Zhang Mengdi, Zhu Zhaohua, Han Weiyu, Chen Qiyue, Ding Changhai
Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
Centre of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
Mater Today Bio. 2023 Jun 17;21:100702. doi: 10.1016/j.mtbio.2023.100702. eCollection 2023 Aug.
Rheumatoid arthritis (RA) is a common chronic inflammatory disease characterized by the proliferation of fibroblast-like synoviocytes (FLS), pannus development, cartilage, and bone degradation, and, eventually, loss of joint function. Fibroblast activating protein (FAP) is a particular product of activated FLS and is highly prevalent in RA-derived fibroblast-like synoviocytes (RA-FLS). In this study, zinc ferrite nanoparticles (ZF-NPs) were engineered to target FAP (FAP positive) FLS. ZF-NPswere discovered to better target FAP FLS due to the surface alteration of FAP peptide and to enhance RA-FLS apoptosis by activating the endoplasmic reticulum stress (ERS) system via the PERK-ATF4-CHOP, IRE1-XBP1 pathway, and mitochondrial damage of RA-FLS. Treatment with ZF-NPs under the influence of an alternating magnetic field (AMF) can significantly amplify ERS and mitochondrial damage via the magnetocaloric effect. It was also observed in adjuvant-induced arthritis (AIA) mice that FAP-targeted ZF-NPs (FAP-ZF-NPs) could significantly suppress synovitis , inhibit synovial tissue angiogenesis, protect articular cartilage, and reduce M1 macrophage infiltration in synovium in AIA mice. Furthermore, treatment of AIA mice with FAP-ZF-NPs was found to be more promising in the presence of an AMF. These findings demonstrate the potential utility of FAP-ZF-NPs in the treatment of RA.
类风湿性关节炎（RA）是一种常见的慢性炎症性疾病，其特征为成纤维细胞样滑膜细胞（FLS）增殖、血管翳形成、软骨和骨降解，最终导致关节功能丧失。成纤维细胞激活蛋白（FAP）是活化FLS的一种特殊产物，在源自类风湿性关节炎的成纤维细胞样滑膜细胞（RA-FLS）中高度表达。在本研究中，工程化制备了靶向FAP（FAP阳性）FLS的锌铁氧体纳米颗粒（ZF-NPs）。由于FAP肽的表面修饰，发现ZF-NPs能更好地靶向FAP FLS，并通过PERK-ATF4-CHOP、IRE1-XBP1途径激活内质网应激（ERS）系统以及导致RA-FLS的线粒体损伤，从而增强RA-FLS的凋亡。在交变磁场（AMF）作用下用ZF-NPs处理可通过磁热效应显著放大ERS和线粒体损伤。在佐剂诱导的关节炎（AIA）小鼠中还观察到，靶向FAP的ZF-NPs（FAP-ZF-NPs）可显著抑制滑膜炎，抑制滑膜组织血管生成，保护关节软骨，并减少AIA小鼠滑膜中M1巨噬细胞浸润。此外，发现在存在AMF的情况下，用FAP-ZF-NPs治疗AIA小鼠更具前景。这些发现证明了FAP-ZF-NPs在类风湿性关节炎治疗中的潜在应用价值。
