2. Academic Validation
  3. 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

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

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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