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 was proposed for prolonged drug delivery and microenvironment remodeling. Nanogel was constructed through 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. Zn2+ 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.This article is protected by copyright. All rights reserved

中文翻译：

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基于 MOF 的自我增强纳米凝胶通过长效药物释放减轻骨关节炎

关节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空间导致药物的快速清除。在此，提出了一种基于纳米凝胶的策略来延长药物输送和微环境重塑。纳米凝胶是通过在负载 Kartogenin (KGN) 的沸石咪唑酯框架 8（表示为 KZIF@HA）表面上通过酰胺反应对透明质酸 (HA) 进行官能化而构建的。利用 HA 固有的亲水性，KZIF@HA 自发形成纳米凝胶，确保药物在 OA 微环境中延长释放。 KZIF@HA 表现出超过一个月的持续药物释放，与 KZIF 相比，关节腔渗漏风险较低，软骨渗透增强，对软骨细胞具有修复作用。值得注意的是，KZIF@HA 释放的 KGN 可促进细胞外基质 (ECM) 分泌，促进透明软骨再生。锌2+释放通过促进 M2 巨噬细胞极化建立抗炎微环境来逆转 OA 进展。最终，KZIF@HA 在三个月内促进软骨再生并缓解骨关节炎。转录组测序证实 KZIF@HA 刺激 M2 巨噬细胞极化并分泌 IL-10 抑制 JNK 和 ERK 通路，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 治疗策略方面取得了重大进步。本文受版权保护。版权所有