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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\u2010life 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\u2010modified PBA NPs\u2010loaded hydrogel (FA\u2010PBA NPs@Gel) with sustained release, injectability, and enhanced stability. FA\u2010PBA NPs@Gel selectively targets M1 macrophages via FA\u2013folate receptor 1 interaction to alleviate synovitis, while disrupting macrophage\u2013chondrocyte 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\u2010PBA NPs@Gel suppressed nuclear factor\u2010\u03baB (NF\u2010\u03baB) activation by binding glycogen synthase kinase 3 beta (GSK3\u03b2), thereby downregulating chemokine ligand 20 (CCL20), disrupting macrophage\u2013chondrocyte crosstalk and promoting cartilage regeneration. In summary, FA\u2010PBA NPs@Gel represent a promising OA therapy with dual functions of mitigating synovitis and promoting regeneration.<\/jats:p>","DOI":"10.1002\/smll.202509306","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T13:26:52Z","timestamp":1761658012000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Betulinic Acid Self\u2010Assembled Nanodelivery System Attenuates Osteoarthritis by Dually Modulating Macrophage Polarization and Macrophage\u2010Chondrocyte Crosstalk via Disruption of the GSK3\u03b2\/NF\u2010\u03baB\/CCL20 Axis"],"prefix":"10.1002","volume":"21","author":[{"given":"Qinwen","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Southern Medical University  Guangzhou Guangdong 510515 P. R. 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