Biphasic oxygen-regulating cyanobacterial hydrogel for synergistic ischemic stroke gas therapy and post-stroke depression prevention

Abstract Ischemic stroke (87% of stroke cases) results from cerebral artery occlusion. Reperfusion therapy restores cerebral blood flow but predisposes to dual complications: ischemia-reperfusion injury (IRI) caused by oxygen fluctuations exacerbating neural damage and post-stroke depression (PSD). This study develops a cyanobacteria hydrogel composite (PT-CUCBD) for comprehensive reperfusion protection through precisely regulating the oxygen (O) microenvironment during distinct reperfusion phases. During pre-reperfusion phase, upconversion nanoparticles emit 660/450 nm light under 808 nm near-infrared irradiation for photosynthetic O production, thereby alleviating pre-reperfusion hypoxia, while ultraviolet light triggers nitric oxide (NO) release to promote angiogenesis. More importantly, during post-reperfusion phase, cessation of irradiation activates cyanobacterial respiration to deplete excess O, mitigating reoxygenation injury. Simultaneously, PT-CUCBD efficiently scavenges reactive oxygen species (ROS), while its loaded diallyl trisulfide releases hydrogen sulfide (HS) in response to glutathione to enhance neuroprotection. Furthermore, it promotes macrophage polarization toward the anti-inflammatory M2-type, suppressing neuroinflammation and apoptosis. Notably, experimental results demonstrate that, this multifunctional platform not only prevents IRI, but also significantly reduces the risk of PSD, establishing a promissing therapeutic paradigm for ischemic stroke.