Contaminants of emerging concern (CEC) have been documented in surface waters, sediment and biota in Southern Ocean. Among CEC, in recent years micro- and nanoplastics and metal-oxide nanomaterials have been found in several environmental compartments. Ecotoxicological consequences to their exposure are almost unknown for Antarctic aquatic species and barely addressed so far. 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 CEC 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/ml). Transcript-target q-RT-PCR was performed with the aim to identify suitable biomarkers of exposure and effects. The experimental exposures showed gene expression profiles with the control group always clustered together (at both concentrations), however, as expected at the highest concentration 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. Although few transcripts were shared as differentially expressed between the experimental treatments compared to control, At function level relevant ones 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 nanoplastics, n-TiO2 and their combination at 50 µg/ml, that could be used for monitoring clams’ health status in different Antarctic localities.