Genetically engineered chondrocyte-mimetic nanoplatform attenuates osteoarthritis by blocking IL-1β and restoring sirtuin-3

  • Sci Adv. 2025 Jul 25;11(30):eadv4238. doi: 10.1126/sciadv.adv4238.
Caifeng Deng  1  2  3 ,  Liukang Yu  1  2  3 ,  Xuan Zhao  1  2  3 ,  Yuxiao Chen  1  2  3 ,  Jiabin Mei  1  2  3 ,  Jie Wei  1  2  3 ,  Xiaoyuan Chen  4  5  6  7  8  9  10  11 ,  Guanghua Lei  1  2  3  12 ,  Chao Zeng  1  2  3  12
Affiliations
  • 1. Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.
  • 2. Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China.
  • 3. Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China.
  • 4. Department of Diagnostic Radiology, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore.
  • 5. Department of Chemical and Biomolecular Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore.
  • 6. Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore.
  • 7. Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore.
  • 8. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 9. Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 10. Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 11. Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore.
  • 12. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
PMID: 40712009 DOI: 10.1126/sciadv.adv4238
Abstract

Osteoarthritis (OA) is a multifactorial disease characterized by joint inflammation and cartilage degeneration, with no disease-modifying drugs available. The vicious cycle between the inflammatory microenvironment (inflamed soil) and dysfunctional chondrocytes (degeneration-related seeds) drives the chronic progressive deterioration of OA. Here, we report a genetically engineered chondrocyte-mimetic nanoplatform (termed HKL-GECM@MPNPs) comprising a honokiol (HKL)-loaded mitochondrion-targeting nanoparticle core coated with an interleukin-1 receptor type 2 (IL-1R2)-overexpressing chondrocyte membrane. HKL-GECM@MPNPs fuse with OA chondrocytes, transferring IL-1R2 onto the plasma membrane and reprogramming the inflamed microenvironment through IL-1β blockade. Mitochondrion-targeting cores then directly deliver HKL to restore mitochondrial sirtuin-3 in OA chondrocytes, reprogramming the cells' pathological phenotype. Intra-articular injection of HKL-GECM@MPNPs in OA mice reduces inflammation, alleviates joint pain, and mitigates cartilage damage through a synergistic effect. Moreover, HKL-GECM@MPNPs effectively reverse cartilage degeneration in human OA cartilage explants. This approach highlights the potential of HKL-GECM@MPNPs to combine IL-1β blockade and mitochondrial sirtuin-3 restoration as a promising strategy for OA treatment.

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