Intravesical instillation of pirfenidone/polydopamine nanoparticles for managing neurogenic bladder post-spinal cord injury by alleviating bladder inflammation and fibrosis

Neurogenic bladder (NB) secondary to spinal cord injury (SCI) progresses from early-stage bladder inflammation to late-stage fibrosis, ultimately resulting in renal dysfunction. However, effective therapeutic options for NB remain limited, and patients currently rely exclusively on catheterization-based management to prevent upper urinary tract deterioration. Polydopamine nanoparticles (PDA NPs), a mussel-inspired polymer formed through the oxidative self-polymerization of dopamine, exhibits inherent bioadhesive properties and notable anti-inflammatory activity. Herein, we develop an intravesical delivery system (PFD@PDA NPs) composed of polydopamine nanoparticles loaded with pirfenidone (PFD), an FDA-approved drug for idiopathic pulmonary fibrosis (IPF), for the localized management of NB. Following intravesical instillation, PFD@PDA NPs can firmly adhere to the bladder wall, traverse the mucosal barrier, and sustain prolonged retention under urinary flow. Mechanistically, PFD@PDA NPs alleviate inflammation by scavenging reactive oxygen species (ROS), targeting mitochondria to protect mitochondrial function, and suppressing ferroptosis, while concurrently inhibiting fibrosis by downregulating TGF-β signaling to reduce fibroblast activation and extracellular matrix deposition. Besides, this localized delivery approach preserves bladder function, protects the upper urinary tract, and minimizes the hepatotoxicity associated with oral PFD. By enabling stage-specific intervention against early-stage bladder inflammation and late-stage fibrosis, this intravesical delivery system offers a clinically translatable approach for managing SCI-induced NB.