Hypoxia-Responsive Self-Assembling Nanoparticles Based on an Amphiphilic Copolymer for Targeted Delivery of Tissue Plasminogen Activator in Acute Mesenteric Ischemia Therapy

Acute mesenteric ischemia (AMI) is a life-threatening disease characterized by the sudden loss of blood flow to the small intestine, leading to ischemia and potentially fatal intestinal necrosis if not promptly addressed. Current treatment protocols prioritize endovascular thrombolysis with a tissue plasminogen activator (tPA) as the first-line intervention. However, the efficacy of tPA is limited by its rapid inactivation in the bloodstream and associated risks of hemorrhagic complications from excessive dosing. Herein, we explored a hypoxia-responsive, cyclic arginyl-glycyl-aspartic acid (cRGD) peptide-decorated amphiphilic copolymer composed of polyethylene glycol (PEG) and poly(propylene glycol)bis(2-aminopropyl ether) (PPG), linked by an azo bond, named cRGD-PEG-azo-PPG (cPaP), which self-assembled to load tPA effectively for AMI therapy. Our results demonstrated that tPA-loaded cPaP nanoparticles can precisely target thrombus sites by cRGD peptide and respond to the hypoxic microenvironment to release the drug by hypoxia-responsive azo bond, significantly improving thrombolytic outcomes in vitro and in vivo. This study demonstrates the potential of utilizing biochemical and environmental triggers for targeted delivery of tPA, significantly improving the safety and efficacy of treatments for thromboembolic disease.