Sequential delivery of sinigrin and dabigatran by an in situ self-stabilizing dynamic hydrogel attenuates intervertebral disc degeneration

Intervertebral disc degeneration (IDD) is characterized by an imbalance between nucleus pulposus catabolism and anabolism, driven by metabolic dysfunction of nucleus pulposus cells (NPCs) and a chronic inflammatory microenvironment. Effective treatments for IDD are lacking. Here, we report an injectable hydrogel that achieves reactive oxygen species (ROS)-triggered self-stabilization within the degenerative microenvironment for adaptive intradiscal therapy. The CAD hydrogel is constructed from chitosan-phenylboronic acid (CS-PBA), aldehyde-β-cyclodextrin (A-β-CD), and hyaluronic acid-dopamine (HA-DA), forming a dynamic multinetwork. The dopamine moieties are preorganized within the network via both boronate ester bonds and host‒guest interactions with β-CD. Upon encountering pathological ROS in the oxidative IDD microenvironment, the cleavage of boronate esters triggers the release of sinigrin (SIN). Moreover, <i>in situ</i> polymerization of the dopamine moieties occurs simultaneously, which is facilitated by the spatial confinement of dopamine by β-CD. Polymerization converts the dynamic network into a covalently stabilized matrix, effectively self-solidifying the hydrogel to counteract mechanical decay and enabling the sustainable release of dabigatran (DAB) encapsulated in β-CD. This process ensures long-term structural support while enabling intelligent dual drug delivery. In a puncture-induced IDD model, the hydrogel demonstrated significant efficacy. <i>In vitro</i>, the dual-drug-loaded DS@CAD hydrogel mitigated NPC inflammatory catabolism and promoted anabolism. Mechanistically, the rapid release of SIN attenuated inflammation by targeting MAPK signalling, while sustained DAB release inhibited inflammation via RELA and promoted extracellular matrix anabolism by activating AMPK. This reconfigurable hydrogel platform offers an innovative strategy for developing next-generation biomaterials that respond to complex disease microenvironments for adaptive therapy.