This study aims to assess the potential toxicity of (1) nanoplastics (NPs) issued from the fragmentation of larger plastic particles collected on the Caribbean marine coast (NP-G), and (2) polystyrene NPs (NP-PS), commonly used in the literature, on Caribbean swamp oysters (Isognomon alatus). Oysters were exposed to 7.5 and 15 mu g.L- 1 of each type of NPs, combined or not with arsenic (As) at 1 mg.L-1 for one week before molecular analyses at gene levels. Overall, the NP-G triggered more significant changes than NP-PS, especially when combined with As. Genes involved in the mitochondrial metabolism were strongly up-regulated in most of the conditions tested (up to 11.6 fold change for the NP-PS exposure at 7.5 mu g.L-1 for the 12s). NPs in combination with As or not triggered a response against oxidative stress, with an intense repression of cat and sod1 (0.01 fold-changes for the NP-G condition at 7.5 mu g.L-1). Both NP-G and NP-PS combined or not with As led to an up-regulation of apoptotic genes p53 and bax (up to 59.3 fold-changes for bax in the NP-G condition with As). Our study reported very innovative molecular results on oysters exposed to NPs from environmental sources. Our results suggest that the composition, surface charge, size, and the adsorbed contaminants of plastics from the natural environment may have synergic effects with plastic, which are underestimated when using manufactured NPs as NP-PS in ecotoxicological studies.