ROS-responsive nanodiscs for STING-NF-κB pathway inhibition and glycosaminoglycan layer restoration in interstitial...

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, refractory bladder disorder characterized by urothelial barrier disruption, chronic inflammation, and oxidative stress. Generally, the deficiency of the glycosaminoglycan (GAG) layer constitutes a core pathological feature of IC/BPS. Although bladder instillation with chondroitin sulfate (CS), a sulfated polysaccharide and a member of the GAG family, has been employed as a conventional replenishment therapy, the clinical efficacy remains limited. This is primarily attributed to its poor mucosal adhesion and retention, rapid clearance due to urinary washout, and accelerated degradation in the highly reactive oxygen species (ROS)-rich bladder microenvironment. Of note, accumulated ROS not only triggers the mitochondrial dysfunction-mediated STING-NF-κB pro-inflammatory pathway but also directly damages the GAG layer, thereby perpetuating an "oxidative damage-repair repression" cycle. Herein, we have engineered a novel two-dimensional multifunctional nanodisc platform by loading CS onto vanadium carbide (V₂C) MXene, followed by surface modification with polyvinyl alcohol (PVA), to construct V₂C MXene-CS@PVA (VMCP), which demonstrates superior bladder mucosal adhesion, overcoming the limited retention time of conventional formulations. In addition, VMCP has been designed for ROS-responsive, on-demand release of CS at sites of oxidative damage. The intrinsic superoxide dismutase (SOD)/catalase (CAT)-mimetic activity of the V₂C MXene core scavenges excessive ROS and alleviates mitochondrial dysfunction, creating a protective antioxidant microenvironment for the released CS. This comprehensive approach enables VMCP to exogenously restore the GAG layer while suppressing the pro-inflammatory STING-NF-κB signaling pathway. Collectively, VMCP nanoplatform synergistically integrates enhanced mucosal adhesion, reduced oxidative stress, and GAG layer reconstruction, proposing a novel therapeutic strategy for IC/BPS management.