Duchenne muscular dystrophy (DMD) is caused by an out-of-frame mutation in the DMD gene that results in the absence of a functional dystrophin protein, leading to a devastating progressive lethal muscle-wasting disease. Muscle stem cell-based therapy is a promising avenue for improving muscle regeneration. However, despite the efforts to deliver the optimal cell population to dystrophic muscles, little is understood on the role endothelial cells play during systemic delivery. Recent single cell RNA sequencing (scRNA-seq) advances has permitted the unraveling of cellular composition and phenotypes in multiple mouse tissues, including skeletal muscle. Here we describe the development of an optimized protocol for systemic delivery of skeletal muscle progenitor cells (SMPCs) which showed limited ability to escape the endothelial barrier in dystrophic and severely dystrophic muscle. To further understand the role of the microenvironment as a barrier to systemic cell delivery to skeletal muscle we explored skeletal muscle-resident cell populations in healthy, dystrophic and severely dystrophic mouse models utilizing scRNA-seq. We found an increased frequency of activated fibroblasts, activated fibro-adipogenic progenitor cells and proinflammatory macrophages in dystrophic and severely dystrophic gastrocnemius muscles. Moreover, employing a computational intercellular interaction method, we show an upregulation of extracellular matrix and platelet aggregation genes on endothelial cells in dystrophic and severely dystrophic muscles. We further show an increased risk of clotting especially in the severely dystrophic environment. This work extends our understanding of the severe nature of DMD, which should be taken into account when considering stem cell-based systemic delivery platforms.