Bladder adaptive hydrogel scaffold with dual release, antimicrobial, immunomodulatory, and repair: DRIVER for urinary...

Urinary tract infections (UTIs), especially complex or recurrent cases, present a significant challenge. Systemic antibiotics often fail to provide adequate local drug concentrations, leading to limited efficacy and relapse. Local delivery is hindered by the bladder's dynamic environment, causing rapid drug clearance. To address this, a hydrogel scaffold, DRIVER (dual release, repair of tissues, immunomodulation, vesical adaptation, elimination of pathogens, and regulation of autophagy), is designed for sustained release in sync with the infection cycle. DRIVER forms a self-regulating 3D network through dynamic bonding and metal ion coordination, ensuring stable release and adaptability. It delivers a biphasic release profile comprising an initial antimicrobial burst that rapidly suppresses acute infection, followed by a 7-day sustained release phase. In vitro, DRIVER retained potent antibacterial and antifungal activity against planktonic, biofilm-embedded, and intracellular pathogens, including drug-resistant strains. Notably, the hydrogel also promoted bladder and kidney repair by modulating mitochondrial activity and autophagy, pathways essential for restoring urothelial integrity. DRIVER achieved >3 log reductions in bacterial and fungal burdens, normalized urinary function, and markedly attenuated systemic and tissue inflammation. Histological analyses confirmed robust architectural recovery in both the bladder and kidney. Together, these findings establish DRIVER as a compelling therapeutic strategy for complex UTIs.