Drug-caged drug: photoredox catalysis-enabled dual decaging of nitric oxide and local anesthetics for simultaneous antibacterial treatment and pain relief

Bacterial infections often result in significant pain, negatively impacting patient outcomes and quality of life. Conventional therapies primarily focus on pathogen eradication but frequently overlook the associated pain, thereby limiting their overall clinical effectiveness. Herein, we propose a 'drug-caged drug' strategy in which the secondary amine group of the local anesthetic tetracaine (TTC) is selectively caged by nitric oxide (NO), forming the TTC-NO prodrug. The TTC-NO prodrug is co-loaded with the photocatalyst fac-Ir(ppy)3 into poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) micellar nanoparticles (TTC-NO@M), enabling dual uncaging of TTC and NO under mild visible light irradiation through a photocatalytic mechanism. We demonstrate that TTC-NO@M exhibits combined antibacterial, anti-inflammatory, and analgesic activities by simultaneously releasing NO and TTC. This strategy effectively treats MRSA-infected mice in both cutaneous wound and septic arthritis models while alleviating infection-associated pain. This work offers a promising approach to address the dual challenges of bacterial infections and the associated pain.