Carnosine-modified gelatin-hyaluronic acid hydrogel comprising fenofibrate-loaded nanoparticles targeting chondrocyte ferroptosis and macrophage polarization for synergistic osteoarthritis therapy.
骨关节炎（OA）是一种致残性和进行性关节疾病，由于软骨细胞铁死亡、慢性滑膜炎症以及传统关节腔内治疗药物的药代动力学局限（如快速清除和滞留性差），其治疗面临重大挑战。为克服这些障碍，我们开发了一种双功能关节腔内递送平台，该平台由包裹载非诺贝特、靶向软骨的纳米颗粒的明胶-透明质酸水凝胶组成（FNPs-GelHA水凝胶）。该系统通过同时抑制软骨细胞铁死亡和调节炎性关节微环境，协同抑制OA进展。体外研究显示，FNPs-GelHA水凝胶可显著减轻软骨细胞铁死亡、炎症、氧化应激和脂质过氧化。此外，该系统通过抑制促炎M1表型并促进修复性M2表型，有效重编程巨噬细胞极化，从而有助于免疫调节和软骨修复。此外，体内实验证明该系统具有延长的关节滞留时间，并在延缓OA进展方面表现出显著的治疗效果。通过整合靶向药物递送、铁死亡抑制和免疫微环境重塑，这种复合水凝胶-纳米颗粒平台为OA治疗提供了一种协同且有前景的策略。
Osteoarthritis (OA), a debilitating and progressive joint disease, presents major therapeutic challenges due to chondrocyte ferroptosis, chronic synovial inflammation, and the pharmacokinetic limitations of conventional intra-articular therapies, such as rapid clearance and poor retention. To overcome these barriers, we developed a dual-functional intra-articular delivery platform composed of a gelatin-hyaluronic acid hydrogel encapsulating fenofibrate-loaded, cartilage-targeting nanoparticles (FNPs-GelHA hydrogel). This system synergistically inhibits OA progression by simultaneously suppressing chondrocyte ferroptosis and modulating the inflammatory joint microenvironment. In vitro studies revealed that FNPs-GelHA hydrogel markedly attenuates chondrocyte ferroptosis, inflammation, oxidative stress, and lipid peroxidation. Furthermore, this system effectively reprograms macrophage polarization by suppressing pro-inflammatory M1 phenotypes and promoting reparative M2 phenotypes, thereby contributing to immunomodulation and cartilage repair. In addition, in vivo experiments demonstrated prolonged joint retention of this system and significant therapeutic efficacy in delaying OA progression. By integrating targeted drug delivery, ferroptosis inhibition, and immune microenvironment remodeling, this composite hydrogel-nanoparticle platform offers a synergistic and promising strategy for OA treatment.
Weibei Sheng, Tianyou Guo, Bo Yu, Jin Zhao, Cehui Hu, Jianjing Lin, et al. Carnosine-modified gelatin-hyaluronic acid hydrogel comprising fenofibrate-loaded nanoparticles targeting chondrocyte ferroptosis and macrophage polarization for synergistic osteoarthritis therapy.. International journal of biological macromolecules. 2026; doi:10.1016/j.ijbiomac.2026.151281.
Weibei Sheng, Tianyou Guo, Bo Yu, Jin Zhao, Cehui Hu, Jianjing Lin, et al (2026). Carnosine-modified gelatin-hyaluronic acid hydrogel comprising fenofibrate-loaded nanoparticles targeting chondrocyte ferroptosis and macrophage polarization for synergistic osteoarthritis therapy.. International journal of biological macromolecules. https://doi.org/10.1016/j.ijbiomac.2026.151281
Weibei Sheng, Tianyou Guo, Bo Yu, Jin Zhao, Cehui Hu, Jianjing Lin, et al. Carnosine-modified gelatin-hyaluronic acid hydrogel comprising fenofibrate-loaded nanoparticles targeting chondrocyte ferroptosis and macrophage polarization for synergistic osteoarthritis therapy.[J]. International journal of biological macromolecules, 2026 doi:10.1016/j.ijbiomac.2026.151281.
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