Extracellular matrix (ECM) consists of proteins, proteoglycans, and different soluble molecules. ECM provides structural support to mammalian cells. ECM is responsible for important cell functions, as well as assembling cells into various tissues and organs, regulating growth and cell-cell interaction. Recent studies have shown the potential of nanostructured biomaterials to mimic native ECM. Developing tailor-made biomaterials that mimic the complex nanoscale mesh of local ECM is not a trivial endeavor: bio-inspired biomaterials are designed to supply a healthy ECMlike structure, capable of filling the lesion cavity, favoring transplanted cell engraftment, providing physical support to endogenous neurogenesis and also tuning the inflammatory response to protect spared neurons. The strategies used to manufacture biomimetic hydrogel scaffold represent particularly important prospects of novel therapies for CNS regeneration. During this review, we describe with details the most promising regulatory pathways from ECM involved in the CNS injury and regeneration and we draw a line to the biomimetic potential of engineered nanostructured biomaterials aimed at mimicking extracellular matrix constructs and favoring the release of pro-regenerative agents. Lastly, a brief overview of their application in clinical trials is provided.