PROJECT SUMMARY/ABSTRACT Despite decades of intensive research, there are currently no disease-modifying therapies to treat spinal cord injury (SCI). One major reason for this dire unmet need is the spatiotemporal heterogeneity of the cells that comprise the injury site. Therapeutic molecules (e.g., small molecules, RNAs, proteins) that target one cell type may be contraindicated for another cell type, thereby masking any potential beneficial effects. In this proposal, we will address this issue by utilizing single-cell transcriptomics and proteomics data of the spinal cord injury site to bioinformatically identify compounds that are predicted to reverse the disease phenotype in a cell-type and cell-state-specific manner. Our research team has recently developed a novel drug discovery platform that integrates single-cell gene expression data with perturbation-response data derived from the NIH Library of Integrated Network-based Cellular Signatures (LINCS) L1000 dataset to identify compounds that target specific cell-types in tissues with diverse cellular heterogeneity. Another challenge that will be addressed in this proposal is that of cell-type specific drug delivery. We will develop an advanced drug delivery system capable of highly efficient cell-type targeted delivery with stimuli-responsive drug release at the spinal cord injury site. These novel technologies will be used to target macrophages and fibroblasts that comprise the fibrotic scar at the spinal cord injury site, which is a major barrier to the regeneration of axons and oligodendrocytes.