Microenvironment-ResponsiveHydrogels Comprising EngineeringZeolitic Imidazolate Framework-8-Anchored Parathyroid Hormone-RelatedPeptide‑1 for Osteoarthritis Therapy

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.