An NIR-Triggered Self-Propelled Janus Nanomotor-Integrated Hydrogel with Enzymatic Cascade Reactions and Photothermal-Enhanced Drug Release for the Treatment of Gouty Arthritis.

Gouty arthritis is characterized by monosodium urate (MSU) crystal deposition, persistent joint inflammation, oxidative stress, and limited drug penetration. Here, we report an injectable hydrogel system embedding asymmetric Janus nanomotors (Col-PLGA@Au-CU) that integrates enzymatic cascade reaction, photothermal propulsion, and on-demand drug release for active gout therapy. The nanomotors consist of colchicine-loaded PLGA cores partially coated with gold nanoshells and functionalized with uricase (UOx) and catalase (CAT), which are encapsulated in a chitosan-based hydrogel for intra-articular retention. Under near-infrared (NIR) irradiation, the gold nanoshells generate localized heat, which accelerates the release of the nanomotors from the hydrogel. The elevated temperature also enhances the UOx/CAT cascade reaction, resulting in increased oxygen generation and enhanced active motion of the nanomotors. Meanwhile, the photothermal effect accelerates the release of colchicine from the hydrogel. The enzymatic cascade not only depletes uric acid but also decomposes H₂O₂ into O₂ and H₂O, relieving oxidative stress and hypoxia. In vitro, the NIR-triggered nanomotors exhibited significantly enhanced cellular uptake, ROS scavenging, HIF-1α suppression, and M2 macrophage polarization. In a murine MSU-induced gout model, intra-articular injection of Col-PLGA@Au-CU@CS hydrogel followed by NIR irradiation effectively reduced joint swelling, restored gait patterns, decreased synovial inflammation, protected cartilage integrity, and downregulated TNF-α and IL-6 expression, without systemic toxicity. This enzyme-powered, photothermal-activatable Janus nanomotor hydrogel represents a controlled-release platform that combines enhanced active transport, microenvironment modulation, and triggered drug delivery, offering a promising strategy for precision therapy of gouty arthritis. STATEMENT OF SIGNIFICANCE: This study presents a novel injectable Janus nanomotor-integrated hydrogel (Col-PLGA@Au-CU@CS) for the treatment of gouty arthritis. By combining an enzymatic cascade (uricase and catalase) with a photothermal gold nanoshell, the system achieves simultaneous uric acid depletion, hydrogen peroxide decomposition, and NIR-triggered self-propulsion. The asymmetric nanomotors overcome poor drug penetration into avascular cartilage, while the hydrogel ensures intra-articular retention. Under NIR irradiation, enhanced directional motion, on-demand colchicine release, and reactive oxygen species scavenging lead to marked suppression of synovial inflammation, M2 macrophage polarization, and cartilage protection in a murine gout model. This work establishes an enzyme-powered, photothermal-activatable platform that integrates active tissue penetration, microenvironment modulation, and triggered drug delivery, offering a promising precision therapy strategy for gouty arthritis and potentially other inflammatory joint diseases.