ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Inflammation Pharmacology
This article is part of the Research TopicInflammation, Healing, and Innovation: Advances in Regenerative Therapies for Enhanced Wound RecoveryView all articles
Oleanolic Acid Cubic Liquid Crystal Nanoparticle-Based Thermosensitive Gel Attenuates Knee Osteoarthritis Symptoms in Rats
Provisionally accepted
- Wuxi Traditional Chinese Medicine Hospital, Wuxi, China
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BACKGROUND: Knee osteoarthritis (KOA) is a prevalent degenerative joint disease with limited effective treatment options. Oleanolic acid (OA) possesses promising anti-inflammatory and cartilage-protective properties, but its clinical application is hindered by poor solubility and rapid metabolism. PURPOSE: This study aimed to develop an oleanolic acid-loaded liquid crystalline nanogel (OANG) for intra-articular delivery and to systematically evaluate its therapeutic effects and potential mechanisms in a rat KOA model. METHODS: OA-loaded nanoparticles were prepared and incorporated into a thermosensitive Poloxamer gel base to form OANG. A papain-induced KOA rat model was established. Rats were administered OANG (high/low dose) intra-articularly, with celecoxib as a positive control. Evaluations included behavioral tests, micro-computed tomography, histological analyses (hematoxylin and eosin, transmission electron microscopy, immunohistochemistry), enzyme-linked immunosorbent assay of synovial fluid, serum, and hippocampus, Western blot (WB), network pharmacology, and molecular docking. RESULTS: OANG exhibited sustained-release properties and improved joint lubrication. Treatment with OANG significantly alleviated KOA-induced pain and depression-like behaviors, reduced cartilage degradation and subchondral bone sclerosis, and downregulated levels of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6) and cartilage degradation markers (C-terminal cross-linked telopeptide of type II collagen, cartilage oligomeric matrix protein) in synovial fluid. It also enhanced antioxidant capacity (increased superoxide dismutase, glutathione peroxidase; decreased malondialdehyde) and modulated the expression of key cartilage proteins (increased Collagen II; decreased matrix metalloproteinase 13; regulated glycogen synthase kinase-3β/SRY-box transcription factor 9, β-catenin, and Yes-associated protein). Furthermore, OANG ameliorated hippocampal oxidative stress and inflammation (decreased Cleaved caspase-3, Malondialdehyde; increased IL-10). Network pharmacology and docking suggested the involvement of peroxisome proliferator-activated receptor gamma, mitogen-activated protein kinase 3, prostaglandin-endoperoxide synthase 2, and pathways such as estrogen signaling and cyclic adenosine monophosphate signaling.
Keywords: gel, knee osteoarthritis, Nanoparticles, Oleanolic Acid, pharmacology.
Received: 22 Oct 2025; Accepted: 28 Nov 2025.
Copyright: © 2025 Shi, Li, Jia and Tang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zhiqi Shi
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