Intra-articular drug injections are effective for osteoarthritis (OA), but challenges such as the complex microenvironment and rapid drug diffusion require frequent injections. Herein, we propose a biofunctional hydrogel-based strategy for prolonged drug delivery and microenvironment remodeling. We propose a strategy to functionalize zeolitic imidazolate framework-8 with tannic acid (TA-ZIF), anchor PTH-related peptide-1 (PTHrP-1) within this framework (TA-ZIF@P1) and incorporate a phenylboronic acid-modified gelatin-based hydrogel (GP hydrogel) drug delivery system (GP@TA-ZIF@P1, GPTP hydrogel) with responsive release properties that respond to the pathological microenvironments of OA. The GPTP hydrogel facilitated controlled, sustained release of PTHrP-1 via dynamic boronic esters, with in vitro and in vivo studies showing continuous release for over 28 days. It not only promotes chondrocyte proliferation but also exhibits significant cytoprotective effects under hyperactive ROS and IL-1β-induced conditions. Notably, transcriptome sequencing confirms that the GPTP hydrogel facilitates both chondrocyte proliferation and chondrogenesis under inflammatory conditions by deactivating Wnt/β-Catenin signaling pathways and enhancing the PI3K/AKT signaling pathway. Additionally, the GPTP hydrogel delays the catabolic metabolism of cartilage explants from mice in inflammatory environments. In a surgical model of mouse OA, we show that the intra-articular injection of GPTP hydrogels reduced periarticular bone remodeling and promoted the production of glycosaminoglycans while offering chondroprotection against cartilage degeneration. To sum up, this pioneering research on PTHrP-1 as a treatment for OA, combined with the GPTP hydrogel system, offers valuable insights and a paradigm for the controlled and sustained release of PTHrP-1, representing a significant advancement in OA treatment strategies.

中文翻译：

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微环境响应性水凝胶，包含工程沸石咪唑酯框架-8-锚定甲状旁腺激素相关肽-1，用于骨关节炎治疗


关节内注射药物对骨关节炎 （OA） 有效，但复杂的微环境和药物快速扩散等挑战需要频繁注射。在此，我们提出了一种基于生物功能水凝胶的策略，用于延长药物递送和微环境重塑。我们提出了一种策略，用单宁酸 （TA-ZIF） 将沸石咪唑酯框架 8 功能化，在该框架内锚定 PTH 相关肽-1 （PTHrP-1） （TA-ZIF@P1），并掺入苯硼酸修饰的明胶基水凝胶 （GP 水凝胶） 药物递送系统 （GP@TA-ZIF@P1，GPTP 水凝胶） 具有响应性释放特性，可响应 OA 的病理微环境。GPTP 水凝胶通过动态硼酸酯促进了 PTHrP-1 的受控、持续释放，体外和体内研究表明连续释放超过 28 天。它不仅促进软骨细胞增殖，而且在过度活跃的 ROS 和 IL-1β 诱导的条件下表现出显着的细胞保护作用。值得注意的是，转录组测序证实，GPTP 水凝胶通过停用 Wnt/β-Catenin 信号通路并增强 PI3K/AKT 信号通路，在炎症条件下促进软骨细胞增殖和软骨形成。此外，GPTP 水凝胶在炎症环境中延迟小鼠软骨外植体的分解代谢。在小鼠 OA 的手术模型中，我们表明 GPTP 水凝胶的关节内注射减少了关节周围骨重塑并促进了糖胺聚糖的产生，同时提供软骨保护以防止软骨退化。 综上所述，这项关于 PTHrP-1 治疗 OA 的开创性研究，结合 GPTP 水凝胶系统，为 PTHrP-1 的控制和持续释放提供了有价值的见解和范式，代表了 OA 治疗策略的重大进步。