Nucleic acids are potential pathogen‐associated or danger‐associated molecular patterns that modulate immune responses and the development of autoimmune disorders. Class A scavenger receptors (SR‐As) are a diverse group of pattern recognition receptors that recognize a variety of polyanionic ligands including nucleic acids. While
SR‐As are important for the recognition and internalization of extracellular ds RNA, little is known about extracellular DNA, despite its association with chronic infections and autoimmune disorders. In this study, we investigated the specificity of and requirement for SR‐As in binding and internalizing different species, sequences and lengths of nucleic acids. We purified recombinant coiled‐coil/collagenous and scavenger receptor cysteine‐rich ( SRCR) domains that have been implicated as potential ligand‐binding domains. We detected a direct interaction of RNAand DNAspecies with the coiled‐coil/collagenous domain, but not the SRCRdomain. Despite the presence of additional surface receptors that bind nucleic acids, SR‐As were found to be sufficient for nucleic acid binding and uptake in A549 human lung epithelial cells. Moreover, these findings suggest that the coiled‐coil/collagenous domain of SR‐As is sufficient to bind nucleic acids independent of species, sequence or length.