Open Access

ARTICLE

Synergistic Therapy of Knee Osteoarthritis Using Amphiphilic ROS-Responsive Nanoparticles Loaded with Celecoxib

Qing Yang¹, Yi Yang^2,*, Jia Yang^3,*
1 Orthopedics Department, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
2 Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming, China
3 Department of Orthopedics, Kunming Children’s Hospital, Kunming, China
* Corresponding Author: Yi Yang. Email: ; Jia Yang. Email:
(This article belongs to the Special Issue: Polymer Materials in Controlled Drug Delivery)

Journal of Polymer Materials https://doi.org/10.32604/jpm.2026.077474

Received 10 December 2025; Accepted 09 April 2026; Published online 14 May 2026

Abstract

The pathological progression of knee osteoarthritis (KOA) is closely associated with synovial inflammation and a microenvironment characterized by excessive reactive oxygen species (ROS). Celecoxib (CEL), a commonly used cyclooxygenase-2 inhibitor suffers from poor targeting and systemic side effects when administered systemically. To achieve precise drug delivery and synergistic therapy at the joint lesion site, this study designed and synthesized an amphiphilic poly (2-oxazoline) block copolymer (POxSP) with a thioketal-based ROS-responsive linker. This polymer was used to construct intelligent nanoparticles (POxSP-CEL) loaded with CEL. These nanoparticles self-assembled in aqueous solution to form spherical structures with an average size of approximately 92.3 nm and uniform distribution, exhibiting rapid disassembly and drug release under high ROS conditions. In vitro cellular experiments demonstrated that POxSP-CEL was effectively internalized by macrophages. Through a dual synergistic mechanism involving ROS-triggered drug release and ROS consumption by the carrier, it significantly inhibited the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and promoted the expression of the anti-inflammatory cytokine IL-10 in lipopolysaccharide-activated macrophages, effectively reversing the macrophage phenotype from pro-inflammatory M1 to anti-inflammatory M2. In a rat KOA model induced by sodium monoiodoacetate (MIA), intra-articular injection of POxSP-CEL significantly ameliorated cartilage degeneration, reduced proteoglycan loss, and decreased the levels of inflammatory factors in joint tissues. Its therapeutic efficacy was markedly superior to that of free CEL and non-responsive nano-formulations, with no observable significant systemic toxicity. This study confirms that the ROS-responsive POxSP-CEL nano-delivery system not only enables targeted and controlled release of CEL in inflamed joints but also exerts a synergistic therapeutic effect by actively regulating the oxidative stress microenvironment and immune cell function, providing a novel strategy with clinical translation potential for the local and efficient treatment of KOA.

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Keywords

Knee osteoarthritis; ROS-responsive; nanodrug delivery; celecoxib; macrophage polarization; synergistic therapy

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