Under-Urine-Adhered Supramolecular Hydrogel with Linearly Sustained Quercetin Release Facilitates Hemorrhagic Cystitis Healing via Inflammation Regulation

The clinical management of hemorrhagic cystitis remains challenging because of persistent inflammation and bladder mucosal barrier disruption. Although intravesical therapies, such as quercetin and hyaluronic acid (HA), show potential, their efficacy is limited by rapid urinary clearance. Hydrogels offer potential as sustained-release drug carriers and protective barriers, yet designing adhesive hydrogels with optimal wet tissue adhesion, controlled degradation, and regulation of anti-inflammation remains difficult. Here it is aimed to develop a supramolecular gelatin-based hydrogel adhesive (HADA/gelatin/Ac-β-CD/quercetin, HGCQ) that combines acrylated β-cyclodextrin as a dynamic crosslinker and hydrophobic drug carrier with dopamine-functionalized HA for enhanced tissue adhesion and antioxidant functionality. The HGCQ hydrogel exhibits controlled degradation in artificial urine with sustained quercetin release over 48 h, exceptional burst pressure tolerance of up to 18.8 kPa on the bladder, and rapid hemostatic capability with a clotting time of 15 s. Crucially, HGCQ demonstrates comprehensive therapeutic effects including pro-angiogenic potential, and broad-spectrum antimicrobial efficacy, potent reactive oxygen species scavenging with a clearance of 600 µm H₂O₂, and anti-inflammatory activity mediated by nuculear factor kappa-B (NF-κB)/interleukin (IL)-17 pathways. In hemorrhagic cystitis models, HGCQ restores urothelial barrier function, promotes collagen III deposition, and reduces inflammation, making a significant advancement in managing this condition with potential applications in other wound healing scenarios.