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Graphene-based materials (GBMs) hold strong promise to restore the spinal cord microenvironment and promote functional recovery after spinal cord injury (SCI). Nanocomposites consisting of reduced graphene oxide (rGO) and adipose tissue-derived extracellular matrix (adECM) are known to promote neuronal growth in vitro and to evoke a biocompatible response in vivo when implanted on top of the intact spinal cord. In this study, pristine adECM and adECM-rGO nanocomposites are implanted directly after hemisection SCI in rats. Scaffolds composed of collagen type I (COL) are applied as negative control, based on evidence that COL triggers integrin-mediated astrogliosis. However, COL scaffolds induce orthotopic bone formation in the lesion site and are therefore excluded from further analyses. Compared to pristine adECM, adECM-rGO nanocomposites completely restore spinal cord integrity. Macrophage-mediated uptake and clearance of rGO remnants is observed as early as 3 weeks post-implantation. Nanocomposites show an elevated presence of βIII-tubulin-positive axons in the host-material interface after 8 weeks, yet scaffold penetration by axons is only occasionally observed. This is partially due to an increased expression of chondroitin sulfate proteoglycans (CSPGs) within the nanocomposites, even though reactive astrogliosis is unaltered. Despite the complete restoration of tissue architecture, adECM-rGO treatment does not significantly improve functional recovery., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)