An esterase-activatable nanoprodrug mitigates severe spinal cord injury via alleviating ferroptosis and reprogramming inflammatory microenvironment

Spinal cord injury (SCI) is a devastating condition with limited efficacious treatment options. Recent research has revealed the potential of functional nanomedicines to inhibit ferroptosis and reduce inflammatory response, offering a promising therapeutic approach for SCI. Urolithin A (UA) exhibits outstanding antioxidant and anti-inflammatory properties in different neurodegenerative disorders. Intriguingly, whether UA can antagonize ferroptosis remains unknown, and its specific impact on SCI and underlying mechanisms have not been extensively explored. Given the pathological response of esterase overexpression in the SCI microenvironment, taken advantages of nanotechnology in precise targeted delivery, flexible structure design and effective enhancement of drug metabolism pathways, in this study, a novel silica-based integrated nanocarrier is constructed by incorporating carbamate-bridged UA into silica nanoparticles. The resulting PEGylated UA silicon hybrid NPs (PUASi NPs) are sensitive and could be specifically recognized and cleaved by esterase. The findings from both in vitro and in vivo experiments demonstrate that the continuous release of UA from PUASi NPs exhibits notable anti-ferroptotic and anti-inflammatory effects, thus contributing to the improvement of functional recovery in mice suffering from SCI. Collectively, this esterase-activatable nanoprodrug strategy offers an alternative therapeutic regimen for clinical intervention in SCI, with promising prospects for translation into clinical practice.