A Bioinspired Manganese-Organic Framework Ameliorates Ischemic Stroke through its Intrinsic Nanozyme Activity and Upregulating Endogenous Antioxidant Enzymes

Following stroke, oxidative stress induced by reactive oxygen species (ROS) aggravates neuronal damage and enlarges ischemic penumbra, which is devastating to stroke patients. Nanozyme-based antioxidants are emerging to treat stroke through scavenging excessive ROS. However, most of nanozymes cannot efficiently scavenge ROS in neuronal cytosol and mitochondria, due to low-uptake abilities of neurons and barriers of organelle membranes, significantly limiting nanozymes' neuroprotective effects. To overcome this limitation, a manganese-organic framework modified with polydopamine (pDA-MNOF), capable of not only mimicking catalytic activities of natural SOD2's catalytic domain but also upregulating two endogenous antioxidant enzymes in neurons is fabricated. With such a dual anti-ROS effect, this nanozyme robustly decreases cellular ROS and effectively protects them from ROS-induced injury. STAT-3 signaling is found to play a vital role in pDA-MNOF activating the two antioxidant enzymes, HO1 and SOD2. In vivo pDA-MNOF treatment significantly improves the survival of middle cerebral artery occlusion (MCAo) mice by reducing infarct volume and more importantly, promotes animal behavioral recovery. Further, pDA-MNOF activates vascular endothelial growth factor expression, a downstream target of STAT3 signaling, thus enhancing angiogenesis. Taken together, the biochemical, cell-biological, and animal-level behavioral data demonstrate the potentiality of pDA-MNOF as a dual ROS-scavenging agent for stroke treatment.

Automated summary

After stroke, reactive oxygen species (ROS) cause oxidative stress, leading to neuronal damage and expansion of the damaged area, which is devastating to stroke patients. Nanozyme-based antioxidants have emerged as a potential treatment to scavenge ROS. However, the limited uptake abilities of neurons and barriers of organelle membranes hinder the efficient scavenging of ROS by most nanozymes, reducing their neuroprotective effects. To overcome this limitation, a novel nanozyme called pDA-MNOF is developed, which not only mimics the catalytic activities of a natural antioxidant enzyme but also enhances the production of two endogenous antioxidant enzymes in neurons. This dual anti-ROS effect of pDA-MNOF effectively reduces cellular ROS levels and protects neurons from ROS-induced injury. In vivo experiments show that pDA-MNOF treatment improves the survival of stroke mice by reducing the size of the damaged area and promoting behavioral recovery. Furthermore, pDA-MNOF activates a signaling pathway that enhances blood vessel formation, providing additional benefits for stroke treatment. The findings highlight the potential of pDA-MNOF as a dual ROS-scavenging agent for stroke therapy.