Betulinic Acid Self-Assembled Nanodelivery System Attenuates Osteoarthritis by Dually Modulating Macrophage Polarization and Macrophage-Chondrocyte Crosstalk via Disruption of the GSK3β/NF-κB/CCL20 Axis

  • Small. 2025 Oct 28:e09306. doi: 10.1002/smll.202509306.
Qinwen Liu  1  2 ,  Yupeng Chen  3 ,  Xiaoyan Zhuang  1  2 ,  Jingxin Liu  1  2 ,  Haojie Chen  1  2 ,  Zhenyi Shi  1  2 ,  Xiang Li  1  2 ,  Yiwen Li  1  2 ,  Qian Luo  1  2 ,  Hangtian Wu  4 ,  Yanpeng Lin  5 ,  Wanling He  1  2 ,  Ruojing Yu  1  2 ,  Yi Li  1  2 ,  Xiaohong Gong  6 ,  Maolin Wang  7 ,  Jun Wang  8 ,  Jianjun Chen  9 ,  Aiping Lu  3 ,  Cheng Zhou  10 ,  Daogang Guan  1  2
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China.
  • 2. Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China.
  • 3. Institute of Systems Medicine and Health Sciences, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, P. R. China.
  • 4. Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China.
  • 5. Department of Radiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China.
  • 6. Department of Rheumatology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450000, P. R. China.
  • 7. Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, 515021, P. R. China.
  • 8. School of Medicine, Foshan University, Foshan, Guangdong, 528000, P. R. China.
  • 9. College of Life Science, Henan Normal University, Xinxiang, Henan, 453007, P. R. China.
  • 10. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China.
PMID: 41146595 DOI: 10.1002/smll.202509306
Abstract

Osteoarthritis (OA) is a degenerative joint disease characterized by M1 macrophage-driven synovitis, worsening progression. In this study, it is found that betulinic acid (BA), a natural compound, inhibits M1 macrophage characteristics while promoting conversion to the M2 phenotype. However, BA suffers from poor solubility and a short half-life in vivo, restricting therapeutic use. Here, a thermosensitive hydrogel is developed using hydroxypropyl chitosan, loaded with poly(betulinic acid) nanoparticles (PBA NPs) and a folic acid (FA) targeting moiety, yielding FA-modified PBA NPs-loaded hydrogel (FA-PBA NPs@Gel) with sustained release, injectability, and enhanced stability. FA-PBA NPs@Gel selectively targets M1 macrophages via FA-folate receptor 1 interaction to alleviate synovitis, while disrupting macrophage-chondrocyte crosstalk to foster cartilage regeneration. Immunofluorescence and flow cytometry demonstrate reprogramming of M1 to M2. Transcriptome Sequencing, antibody microarrays, and drug affinity responsive target stability assays show that FA-PBA NPs@Gel suppressed nuclear factor-κB (NF-κB) activation by binding glycogen synthase kinase 3 beta (GSK3β), thereby downregulating chemokine ligand 20 (CCL20), disrupting macrophage-chondrocyte crosstalk and promoting cartilage regeneration. In summary, FA-PBA NPs@Gel represent a promising OA therapy with dual functions of mitigating synovitis and promoting regeneration.

Keywords
betulinic acid; macrophage metabolic reprogramming; osteoarthritis; targeted delivery.
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