Sun Yun, Ding Sheng-Long, Zhao Xiyuan, Sun Dadi, Yang Yuhan, Chen Min, Zhu Chunlin, Jiang Bingyin, Gu Qi, Liu Huiyu, Zhang Mingzhu
Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Organic-Inorganic Composites, Bionanomaterials & Translational Engineering Laboratory, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, China.
Department of Foot and Ankle Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
Adv Mater. 2024 Sep;36(39):e2401094. doi: 10.1002/adma.202401094. Epub 2024 Jul 3.
Intra-articular injection of drugs is an effective strategy for osteoarthritis (OA) treatment. However, the complex microenvironment and limited joint space result in rapid clearance of drugs. Herein, a nanogel-based strategy is proposed for prolonged drug delivery and microenvironment remodeling. Nanogel is constructed through the functionalization of hyaluronic acid (HA) by amide reaction on the surface of Kartogenin (KGN)-loaded zeolitic imidazolate framework-8 (denoted as KZIF@HA). Leveraging the inherent hydrophilicity of HA, KZIF@HA spontaneously forms nanogels, ensuring extended drug release in the OA microenvironment. KZIF@HA exhibits sustained drug release over one month, with low leakage risk from the joint cavity compared to KZIF, enhanced cartilage penetration, and reparative effects on chondrocytes. Notably, KGN released from KZIF@HA serves to promote extracellular matrix (ECM) secretion for hyaline cartilage regeneration. Zn release reverses OA progression by promoting M2 macrophage polarization to establish an anti-inflammatory microenvironment. Ultimately, KZIF@HA facilitates cartilage regeneration and OA alleviation within three months. Transcriptome sequencing validates that KZIF@HA stimulates the polarization of M2 macrophages and secretes IL-10 to inhibit the JNK and ERK pathways, promoting chondrocytes recovery and enhancing ECM remodeling. This pioneering nanogel system offers new therapeutic opportunities for sustained drug release, presenting a significant stride in OA treatment strategies.
关节腔内注射药物是治疗骨关节炎（OA）的有效策略。然而，复杂的微环境和有限的关节间隙导致药物迅速清除。在此，我们提出了一种基于纳米凝胶的策略，用于延长药物递送和重塑微环境。通过在负载软骨生成素（KGN）的沸石咪唑酯骨架-8（表示为KZIF）表面进行酰胺反应，对透明质酸（HA）进行功能化修饰，构建纳米凝胶（KZIF@HA）。利用HA固有的亲水性，KZIF@HA自发形成纳米凝胶，确保在OA微环境中延长药物释放。KZIF@HA表现出超过一个月的持续药物释放，与KZIF相比，从关节腔泄漏的风险较低，增强了软骨渗透，并对软骨细胞具有修复作用。值得注意的是，从KZIF@HA释放的KGN有助于促进细胞外基质（ECM）分泌，以实现透明软骨再生。锌的释放通过促进M2巨噬细胞极化来逆转OA进展，从而建立抗炎微环境。最终，KZIF@HA在三个月内促进软骨再生并减轻OA症状。转录组测序验证了KZIF@HA刺激M2巨噬细胞极化并分泌IL-10以抑制JNK和ERK途径，促进软骨细胞恢复并增强ECM重塑。这种开创性的纳米凝胶系统为持续药物释放提供了新的治疗机会，在OA治疗策略方面迈出了重要一步。
