ModDetect™ monoclonal antibody panels, originally developed for the detection and quantification of antisense oligonucleotides (ASOs), have now been optimized for use with small interfering RNA (siRNA). siRNAs represent a rapidly growing class of RNA therapeutics that rely on RNA interference to silence disease-causing genes, with several FDA-approved drugs already on the market. This application guide outlines a sandwich ELISA protocol using ModDetect antibodies to sensitively detect siRNA chemical modifications independent of sequence. The method was validated using the FDA-approved siRNA drug Lumasiran, demonstrating how ModDetect can provide reliable quantification even for molecules with fewer PS linkages than typical ASOs.