Modulating the inflammatory cerebral microenvironment via RNA interference holds great potentials for managing post-stroke ischemia-reperfusion (IR) injury. Herein, biomimetic nanocomplexes (NCs) cloaked with platelet-microglia hybrid membrane (HM) are developed to mediate microglia-targeted sphingosine kinase 1 siRNA (siSPHK-1) delivery against cerebral IR injury. The NCs consist of a cationic nano-core assembled from ROS-degradable, branched poly(β-amino ester) (BS) and siSPHK-1, and an outer shell of HM. After intravenous administration, the NCs accumulate at the lesion site due to platelet membrane (PM)-assisted microthrombus targeting, penetrate blood-brain barrier due to CD29-assisted transendothelial migration, and enter microglia via CD51/61-assisted homotypic targeting and CD29-assisted, receptor-mediated endocytosis. The over-produced ROS inside inflamed microglia triggers BS degradation and siSPHK-1 release, thereby provoking SPHK-1 silencing to remodel the inflammatory microenvironment, protect the neurovascular unit, and recover the cognitive/memory ability of IR-injured mice. This study reports a bio-inspired strategy to overcome the multiple physiological barriers against cerebral siRNA delivery, and renders promising implications for gene therapy against cerebral diseases.