Intervertebral disc degeneration (IDD) is a common skeletal disease that accounts for 90% of spine procedures in the clinics [1]. Mainstream IDD therapies consist of both conservative measures such as non-steroidal anti-inflammatory drugs (NSAIDs) and surgical procedures such as discectomy [2]. Although these methods can alleviate pain symptoms, they are unable to completely restore the biological integrity and biomechanical characteristics of intervertebral disc (IVD) or delay IDD progression. Besides, most patients experience recurrent herniation and further degeneration of the adjacent discs after discectomy [3]. Thus, there is a pressing need for developing effective and durable IDD treatments.

Inflammation and oxidative stress are two major contributing factors to the pathophysiology of IDD. Excessive reactive oxygen species (ROS) can trigger mitochondrial membrane depolarization and cause Ca2+ overload and electron leakage, ultimately resulting in mitochondrial dysfunction and metabolic disorders [4]. The energy homeostasis disruption and DNA damage caused by oxidative stress may further lead to irreversible cell cycle arrest, cellular senescence, and cell function loss [5]. IVD damage can be caused by a variety of factors such as trauma, mechanical stress, etc, which would significantly upregulate the secretion of pro-inflammatory cytokines by nucleus pulposus cells (NPCs). These cytokines would further drive the production of catabolic molecules including disintegrins and matrix metalloproteinases (MMPs). Consequently, extracellular matrix (ECM) components such as aggrecan (ACAN) and type II collagen (Col II) within the nucleus pulposus (NP) tissue would undergo progressive degradation, thus aggravating IVD degeneration. NSAIDs are recognized as a first-line treatment of IDD in the clinic [9]. Among the various NSAIDs, celecoxib is the most commonly used drug for IDD treatment [10], which can alleviate oxidative stress and inflammation [[11], [12], [13]]. However, the limited blood supply to IVDs restricts the amount of hydrophobic celecoxib that can reach the discs following oral administration [14], while systemic medications still pose certain risks, such as cardiovascular and gastrointestinal toxicity [15,16]. In recent years, advancements in nanoengineered biomaterials have introduced alternative strategies for direct drug delivery to IVDs [17]. Notably, polydopamine (PDA) nanoparticles have garnered significant attention owing to their excellent biocompatibility and antioxidant capabilities [18]. Therefore, utilizing PDA nanoparticles as carriers may not only enhance the bioavailability of celecoxib to degenerative IVDs but also facilitate more precise and efficient treatment of IDD for minimizing toxic side effects.

However, IVDs are closed tissues, and repeated invasive intra-disc drug injections may cause unneglectable structural damage and raise the risk of infection and leakage of the injected therapeutics, making it difficult to maintain the drug concentration in the IVD above the effective threshold [19]. Hydrogels have garnered increasing interest in the field of IVD repair in the past few years, on account of NP-mimetic composition and structural properties as well as their sustained drug release characteristics [20]. However, traditional drug-loaded hydrogels lack dynamic adaptability and responsiveness. Of note, their drug release rate often fails to match the degradation rate as degeneration progresses, while their mechanical properties frequently suffer irreversible losses under force loading. Recently, microenvironment responsive drug-loaded hydrogels based on dynamic covalent bonds such as Schiff base linkers and boronic ester bonds have been proposed, which can release drugs in response to local microenvironment after injection [21,22]. However, single-responsive hydrogels only target one particular signal of the IDD microenvironment, which may lead to a mismatch between drug release and pathological processes, as well as inadequate amelioration of the aberrant microenvironment. On account of the dominant microenvironmental features of degenerative IVD including high-ROS and low-pH [23,24]. Based on the insights above, this study aims to develop a hydrogel with dual dynamic bonding network, which has intricate responsiveness to high ROS and low pH for on-demand deliver of celecoxib-loaded PDAs for the cooperative regulation of both COX2-PGE2-NFκB and TNFα-P38-MAPK pathways.

In this work, we report a dynamic hydrogel-based drug delivery system (HPPC) for effective IDD therapy, which was constructed through the multi-dynamic bonding among adipic dihydrazide and 3-aminophenylboronic acid hydrochloride modified hyaluronic acid (HA-ADH-PBA), aldehyde-functionalized polyethylene glycol (PEG-FBA), and celecoxib-loaded PDA (CLX@PDA) (Scheme 1). Owing to the dynamic bonding network, HPPC readily responded to the pathological microenvironment of degenerative IVD to mediate efficient celecoxib release while providing mechanical support. To comprehensively evaluate the HPPC hydrogel, we carried out thorough analyses covering chemical composition, structural features, mechanical properties, and antioxidant capabilities. We also carried out in vitro studies to evaluate the biocompatibility and therapeutic efficacy of HPPC hydrogels on NPCs. Subsequently, we designed a rat IDD model and implanted the hydrogel into the IVD for comprehensive radiological and histological evaluations. In addition, high-throughput RNA sequencing and molecular docking analysis revealed that HPPC regulated the COX2-PGE2-NFκB and TNFα-P38-MAPK pathways to alleviate oxidative stress and inflammation in NPCs, thereby contributing to the restoration of damaged IVD. These results provide an approach to improve the anti-inflammatory and anti-oxidative stress effects of celecoxib for superior IVD treatment.