In recent years micro- and nanoplastics and metal-oxide nanomaterials have been found in several environmental compartments. The Antarctic soft clam Laternula elliptica is an endemic Antarctic species having a wide distribution in the Southern Ocean. Being a filter-feeder, it could act as suitable bioindicator of pollution from nanoparticles also considering its sensitivity to various sources of stress. The present study aims to assess the impact of polystyrene nanoparticles (PS-NP) and the nanometal titanium-dioxide (n-TiO2) on genome-wide transcript expression of L. elliptica either alone and in combination and at two toxicological relevant concentrations (5 and 50 µg/L) during 96 h exposure. Transcript-target qRT-PCR was performed with the aim to identify suitable biomarkers of exposure and effects. As expected, at the highest concentration tested, the clustering was clearer between control and exposed clams. A total of 221 genes resulted differentially expressed in exposed clams and control ones, and 21 of them had functional annotation such as ribosomal proteins, antioxidant, ion transport (osmoregulation), acid-base balance, immunity, lipid metabolism, cell adhesion, cytoskeleton, apoptosis, chromatin condensation and cell signaling. At functional level, relevant transcripts were shared among some treatments and could be considered as general stress due to nanoparticle exposure. After applying transcript-target approach duplicating the number of clam samples, four ecologically relevant transcripts were revealed as biomarkers for PS-NP, n-TiO2 and their combination at 50 µg/L, that could be used for monitoring clams’ health status in different Antarctic localities.