Abstract
Revascularization has revolutionized the treatment of ischemic stroke (IS), but its efficacy is limited by cerebral ischemia-reperfusion injury (CIRI). CIRI involves the dynamic interaction of multidimensional pathological mechanisms such as ferroptosis, calcium overload, oxidative stress, and subsequent inflammatory cytokine storm, which make many emerging single-target therapeutic strategies limited in alleviating CIRI. Strategies that simultaneously and synergistically target multiple key pathological factors in CIRI remain highly anticipated but extremely challenging. This study constructed a Sr-substituted Prussian blue (PB)-like nanodrug (SrHCF) as the ultimate multifunctional nanoplatform for the treatment of CIRI. Specifically, SrHCF firstly holds highly active pseudo-superoxide dismutase (SOD)/catalase (CAT) enzymes to effectively eliminate reactive oxygen species (ROS). Secondly, the Fe(3+)-CN-Sr(2+) coordination network of SrHCF efficiently captures Fe(2+) and triggers lattice reconstruction to convert it into PB with stronger antioxidant activity and then thirdly, synchronously releases Sr(2+) to effectively antagonize Ca(2+). Due to this multi-pathway therapeutic coordination mechanism, SrHCF can simultaneously inhibit neuronal ferroptosis, reduce oxidative stress and prevent calcium overload. These synergistic effects enable SrHCF to protect mitochondria and alleviate endoplasmic reticulum stress, ultimately significantly reducing neuronal death and the inflammatory storm caused by the activation of the cGAS-STING pathway of microglia. This study provides a promising paradigm of multi-target synergistic regulation for CIRI treatment.