2. Academic Validation
  3. Targeting CXCL16-expressing macrophages with a biomimetic nanocarrier system attenuates cartilage degeneration in osteoarthritis

Targeting CXCL16-expressing macrophages with a biomimetic nanocarrier system attenuates cartilage degeneration in osteoarthritis

  • J Control Release. 2026 Apr 10:392:114734. doi: 10.1016/j.jconrel.2026.114734.
Qingjun Yang 1,  Yidi Xu 2,  Yang Zhan 3,  Jianping Li 4,  Rui Peng 5,  Bo Yu 6,  Lei Zhang 7,  Guihong Liang 8,  Peng Deng 8,  Houran Cao 8,  Yanhong Han 8,  Zexin Huang 8,  Jianke Pan 8,  Tao Jiang 8,  Weiyi Yang 8,  Yonghong Feng 9,  Xun Huang 10,  Sizhi Wu 11,  Tao Gui 12,  Yongsheng Ye 13
Affiliations

Affiliations

  • 1 Department of Orthopedics, Dongguan Hospital of Traditional Chinese Medicine, Dongguan, Guangdong, China; College of Chinese Materia Medical, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
  • 2 State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Orthopaedics, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Department of Bone and Joint Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China.
  • 3 Gansu University of Chinese Medicine, Lanzhou, Gansu, China.
  • 4 School of Traditional Chinese Medicine and Health, Nanfang College Guangzhou, Guangzhou, Guangdong, China.
  • 5 Department of Bone and Joint Surgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
  • 6 Department of Orthopedics, Medical Innovation Technology Transformation Center of Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China.
  • 7 Department of General Surgery, The Second Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China.
  • 8 State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Orthopaedics, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
  • 9 Department of Orthopedics, Dongguan Hospital of Traditional Chinese Medicine, Dongguan, Guangdong, China.
  • 10 Shandong Provincial Key Laboratory of Detection Technology for Tumor Markers, College of Medicine, Linyi University, Linyi, Shandong, China. Electronic address: [email protected].
  • 11 Department of Gerontology, Guangzhou First People's Hospital, Guangzhou, Guangdong, China; Department of Geriatrics, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong, China. Electronic address: [email protected].
  • 12 State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Orthopaedics, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China. Electronic address: [email protected].
  • 13 Department of Orthopedics, Dongguan Hospital of Traditional Chinese Medicine, Dongguan, Guangdong, China. Electronic address: [email protected].
PMID: 41707770 DOI: 10.1016/j.jconrel.2026.114734
Abstract

Osteoarthritis (OA) is a whole-joint disorder characterized by progressive cartilage degradation and chronic synovial inflammation, in which macrophages play a central role. Using single-cell RNA Sequencing of human and mouse synovial tissues, we identified a pronounced expansion of macrophages during OA progression, with nearly ubiquitous expression of the chemokine CXCL16. These CXCL16+ macrophages exhibited a pro-inflammatory phenotype and were strongly associated with synovitis. To exploit this target, we developed a biomimetic nanoparticle (MAP6) by coating capsaicin-loaded poly(lactic-co-glycolic acid) (PLGA) with CXCR6-enriched M1 macrophage membranes, leveraging the specific CXCL16-CXCR6 interaction. The resulting MAP6 nanoparticles demonstrated enhanced cellular uptake, prolonged synovial retention, and specific targeting of CXCL16+ macrophages in vivo. Furthermore, MAP6 treatment promoted CA2+ influx and NRF2 nuclear translocation, thereby suppressing pro-inflammatory cytokine expression. In a murine OA model, intra-articular administration of MAP6 markedly alleviated synovitis, reduced cartilage degradation, and suppressed the expression of catabolic factors. Collectively, this study highlights CXCL16 as a key macrophage-associated marker in OA and presents a targeted nanotherapeutic strategy capable of modulating synovial inflammation and halting disease progression.

Keywords

CXCL16; CXCR6; Macrophage; Nanocarrier; Osteoarthritis; Synovitis.

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