Triamcinolone acetonide nanoparticles ameliorate interstitial cystitis and anxiety/depression by targeting the bladder-metabolic-brain axis.

Interstitial cystitis (IC) is a refractory bladder disorder for which there are limited therapeutic options due to poorly defined pathogenic mechanisms and suboptimal drug delivery. In addition to bladder pain and urinary dysfunction, patients frequently develop comorbid anxiety and depression. Using metabolomics, we identified D-gulono-1,4-lactone as a pivotal metabolic mediator linking bladder inflammation to neuropsychiatric comorbidities in a cyclophosphamide (CYP)-induced IC mouse model. To target IC, we developed cRGD-functionalized, triamcinolone acetonide (TA)-loaded, pH/ROS dual-responsive nanoparticles (TA/cRGD-CA-αCD NPs) for intravesical delivery. These NPs promoted mucoadhesion, tissue penetration, and responsive drug release, leading to marked amelioration of bladder inflammation, mast cell infiltration, and urinary symptoms. Furthermore, by suppressing hippocampal neuroinflammation, these NPs alleviated anxiety/depression-like behaviors and consequently normalized D-gulono-1,4-lactone levels. Together, these results uncover a bladder-metabolic-brain axis in IC and propose a dual-action therapeutic strategy that simultaneously targets bladder pathology and associated neuropsychiatric symptoms.