As structural components of the glycocalyx, heparan sulfate proteoglycans (HSPGs) are involved in multiple pathophysiological processes at the apex of cell signaling cascades, and as endocytosis receptors for particle structures, such as lipoproteins, extracellular vesicles, and enveloped viruses, including SARS-CoV-2. Given their diversity and complex biogenesis regulation, HSPGs remain understudied. Here we compile some of the latest studies focusing on HSPGs as internalizing receptors of extracellular vesicles (“endogenous virus”) and SARS-CoV-2 lipid-enclosed particles and highlight similarities in their biophysical and structural characteristics. Specifically, the similarities in their biogenesis, size, and lipid composition may explain a common dependence on HSPGs for efficient cell-surface attachment and uptake. We further discuss the relative complexity of extracellular vesicle composition and the viral mechanisms that evolve towards increased infectivity that complicate therapeutic strategies addressing blockade of their uptake.