The microenvironments play a crucial role in secondary injury following spinal cord injury (SCI). Deterioration of the microenvironments, including oxidative stress, inflammation, and excitotoxicity, exacerbates SCI. However, due to the complexity of these microenvironments, synergistic modulation of multiple factors remains challenging. In this study, we developed a reactive oxygen species (ROS) responsive nanoformulation system based on a methoxy poly(ethylene glycol)--poly(L-methionine--L-glutamic acid) copolymer (PME) and loaded it with minocycline (PME@Mino) to promote SCI repair. This nanoformulation was administered intravenously, accumulating at the lesion site where PME@Mino was exposed to ROS, triggering the release of minocycline. Through the synergistic modulation of multiple microenvironment factors, including reduction of oxidative stress, regulation of pro-inflammatory M1 macrophages polarization to anti-inflammatory M2 macrophages, and reduction of calcium ion influx, PME@Mino achieved neuronal and myelin protection. This study highlights advanced approaches for modulating microenvironments using nanoscale treatments for SCI.