Treatment with FAP-targeted zinc ferrite nanoparticles for rheumatoid arthritis by inducing endoplasmic reticulum stress and mitochondrial damage

Weizhong Qi; Li Jin; Cuixi Wu; Hao Liao; Mengdi Zhang; Zhaohua Zhu; Weiyu Han; Qiyue Chen; Changhai Ding

doi:10.1016/j.mtbio.2023.100702

Treatment with FAP-targeted zinc ferrite nanoparticles for rheumatoid arthritis by inducing endoplasmic reticulum stress and mitochondrial damage

Mater Today Bio. 2023 Jun 17:21:100702. doi: 10.1016/j.mtbio.2023.100702. eCollection 2023 Aug.

Authors

Weizhong Qi^{1

2}, Li Jin³, Cuixi Wu¹, Hao Liao², Mengdi Zhang¹, Zhaohua Zhu¹, Weiyu Han^{1

2}, Qiyue Chen⁴, Changhai Ding^{1

5}

Affiliations

¹ Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
² Centre of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
³ Rheumatology and Clinical Immunology, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510282, China.
⁴ Stomatological Hospital, Southern Medical University, Guangzhou, 510282, China.
⁵ Menzies Institute for Medical Research, University of Tasmania, 7000, Hobart, Tasmania, Australia.

Abstract

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 in vivo, 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.

Keywords: Endoplasmic reticulum stress; Magnetic hyperthermia; Mitochondrial damage; Rheumatoid arthritis; Zinc ferrite nanoparticles.