Cerebral ischemia-reperfusion (I/R) injury is exacerbated by the infiltration of splenic monocytes/macrophages (Mo/Mϕ) via the spleen-brain axis, where splenic-derived Mo/Mϕ migrate to cerebral lesions through C-C chemokine ligand 2/receptor 2 (CCL2/CCR2) chemotaxis, thereby amplifying oxidative stress and the neuroinflammatory cascade. Building on this endogenous pathway, we devised a delivery strategy that utilizes splenic Mo/Mϕ as “living vehicles” for targeted drug delivery. To this end, we developed a spleen-targeted magnolol liposome (Mag-PEG₅K) through optimized PEGylation, ensuring its spleen-specific accumulation and uptake by splenic Mo/Mϕ. After cerebral I/R injury, these nanoparticle-laden cells migrate to the ischemic brain via the CCR2/CCL2 axis to remodel the immunomodulatory microenvironment. This targeted system orchestrates dual therapeutic mechanisms within the lesion: mitochondria-directed reactive oxygen species (ROS) scavenging mitigates oxidative stress and peroxisome proliferator-activated receptor gamma (PPARγ) activation reprograms macrophage polarization, suppressing pro-inflammatory M1 differentiation and curtailing tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) secretion. The attenuated cytokine release suppresses neuronal inflammatory cascades, thereby reducing apoptosis. In vivo, Mag-PEG₅K showed superior efficacy to free magnolol, effectively reducing infarct volume and improving long-term neurological outcomes. Supported by favorable biosafety, this work proposes spleen-targeted nanotherapy as an innovative strategy for reprogramming peripheral immunity via the spleen-brain axis, highlighting the translational potential of Mag-PEG₅K for addressing neuroinflammation and oxidative damage in ischemic stroke.

Spleen–brain axis  /  Ischemic stroke  /  Cerebral ischemia–reperfusion injury  /  Magnolol  /  Liposomes  /  Splenic monocytes/macrophages  /  Oxidative stress  /  Macrophage polarization