Tanshinone IIA nano-liposomes ameliorate cerebral ischemia-reperfusion injury associated with activation of the PGK1/Nrf2 signalling axis

Abstract

Ischemic stroke poses a major global health challenge, characterized by high rates of disability and mortality. Although reperfusion therapy serves as an effective strategy to restore cerebral blood flow, it often induces oxidative stress and neuroinflammatory responses that contribute to secondary brain injury. Recent evidence indicates that the PGK1/Nrf2 signaling pathway plays a critical role in mitigating reperfusion injury: PGK1 promotes the nuclear translocation of Nrf2, thereby upregulating protective genes such as heme oxygenase-1 (HO-1) and enhancing endogenous antioxidant defenses. Based on this mechanism, Tanshinone IIA—a multi-target bioactive natural product with known neuroprotective properties—was selected as the therapeutic agent in this study. To overcome its poor penetration across the blood–brain barrier, we successfully developed DSPE-PEG2000-modified Tanshinone IIA liposomes (TADPL). Experimental results demonstrated that this nano-delivery system significantly enhanced drug accumulation in the ischemic cerebral region, improved neurological deficits, and reduced infarct volume in a rat model of middle cerebral artery occlusion (MCAO). Mechanistic studies further confirmed that the neuroprotective effects of TADPL are associated with activation of the PGK1/Nrf2 pathway: the treatment group exhibited enhanced Nrf2 nuclear translocation, upregulation of downstream antioxidant proteins, and markedly reduced levels of oxidative stress markers and inflammatory cytokines. By innovatively integrating nano-delivery technology with signaling pathway modulation, this study not only provides a novel strategy for improving brain-targeted delivery of Tanshinone IIA, but also offers new theoretical insights into its neuroprotective mechanisms, representing a promising candidate for further preclinical development.