Neuroinflammation, commonly associated with various central nervous system (CNS) diseases such as postoperative cognitive dysfunction (POCD), is primarily mediated by the disruption of biological signals in microglia. However, the effective treatment of CNS diseases remains an ongoing challenge as biological signals show limited microglia-targeting effect. In this study, taking advantage of the highly expressed lipoprotein receptor-related protein-1 (LRP1) on the microglia, a nanobiosignal delivery system modified by LRP1 high-affinity peptide ligand RAP12 (RAP: receptor-associated protein) was constructed to specifically regulate neuroinflammation via targeting microglia. The uptake of the RAP12 modified-nanobiosignaler by microglia increased significantly, indicating its microglia-targeting ability. Both in vitro/vivo studies proved that the “nanobiosignaler” significantly reduced the secretion of pro-inflammatory cytokines, induced specific M2 (anti-inflammatory type) microglia differentiation, and remarkably alleviated cognitive function impairment in the mice model when compared with unmodified groups. It was indicated that the “nanobiosignaler” could target microglia to deliver the biological signal and inhibit the excessive activation of microglia. Overall, the cell-targeted biological signal transmission system inspired by “nanobiosignaler” has broad application prospects in the future.