2. Academic Validation
  3. A Dual-Targeted Metal-Organic Framework Based Nanoplatform for the Treatment of Rheumatoid Arthritis by Restoring the Macrophage Niche

A Dual-Targeted Metal-Organic Framework Based Nanoplatform for the Treatment of Rheumatoid Arthritis by Restoring the Macrophage Niche

  • ACS Nano. 2023 Jul 10. doi: 10.1021/acsnano.3c03828.
Siyue Tao 1 2,  Hao Yu 3,  Tao You 4,  Xiangxi Kong 1 2,  Xiaoan Wei 1 2,  Zeyu Zheng 1 2,  Lin Zheng 1 2,  Zhenhua Feng 1 2,  Bao Huang 1 2,  Xuyang Zhang 1 2,  Feng Chen 4,  Xiao Chen 4,  Haixin Song 1 2,  Jie Li 5,  Binhui Chen 5,  Jian Chen 1 2 6,  Qingqing Yao 3,  Fengdong Zhao 1 2 6
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016 Zhejiang, China.
  • 2 Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, 310016 Zhejiang, China.
  • 3 National Engineering Research Center of Ophthalmology and Optometry, School of Ophthalmology & Optometry, Eye Hospital, Wenzhou Medical University, 270 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang, China.
  • 4 The First Affiliated Hospital of USTC, Division of Life Science and Medicine, and CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, 230026 Anhui, China.
  • 5 Department of Orthopaedic Surgery, Ningbo Medical Center Li Huili Hospital, Ningbo, 315100 Zhejiang, China.
  • 6 Department of Orthopedic Surgery, Wenzhou Medical University First Affiliated Hospital, Wenzhou, 325000 Zhejiang, China.
PMID: 37429012 DOI: 10.1021/acsnano.3c03828
Abstract

Inflammatory infiltration and bone destruction are important pathological features of rheumatoid arthritis (RA), which originate from the disturbed niche of macrophages. Here, we identified a niche-disrupting process in RA: due to overactivation of complement, the barrier function of VSIg4+ lining macrophages is disrupted and mediates inflammatory infiltration within the joint, thereby activating excessive osteoclastogenesis and bone resorption. However, complement antagonists have poor biological applications due to superphysiologic dose requirements and inadequate effects on bone resorption. Therefore, we developed a dual-targeted therapeutic nanoplatform based on the MOF framework to achieve bone-targeted delivery of the complement inhibitor CRIg-CD59 and pH-responsive sustained release. The surface-mineralized zoledronic acid (ZA) of ZIF8@CRIg-CD59@HA@ZA targets the skeletal acidic microenvironment in RA, and the sustained release of CRIg-CD59 can recognize and prevent the complement membrane attack complex (MAC) from forming on the surface of healthy cells. Importantly, ZA can inhibit osteoclast-mediated bone resorption, and CRIg-CD59 can promote the repair of the VSIg4+ lining macrophage barrier to achieve sequential niche remodeling. This combination therapy is expected to treat RA by reversing the core pathological process, circumventing the pitfalls of traditional therapy.

Keywords

complement system; macrophage niche; metal−organic framework; osteoclast; pH-responsive materials; rheumatoid arthritis.

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