Abstract: To investigate the impact of symbiotic algae presence or absence on the tolerance of Hydra sinensis to polystyrene nanoparticles (PS NPs), we conducted a 48h acute toxicity experiment on both symbiotic and aposymbiotic strain of H. sinensis using different PS NPs concentrations (20 nm in diameter). The results showed that the 48h half-lethal concentration (48h LC₅₀) for the symbiotic strain (3.36×10² mg/L) was significantly higher than that of the aposymbiotic strain (1.39×10² mg/L). Subsequently, following exposure to a medium containing 75 mg/L PS NPs for 48h, both symbiotic and aposymbiotic strains underwent transcriptomic analysis, respectively (with a control group having 0 PS NPs). A total of 1532 differentially expressed genes (DEGs) were identified in the symbiotic strain between the PS NPs-treated and control groups, with 763 were up-regulated and 769 down-regulated genes. Similarly, 1079 differentially expressed genes (DEGs) were obtained between PS NPs-treated and control group of the symbiotic strain, with 476 up-regulated and 603 down-regulated genes. KEGG enrichment analysis revealed significant enrichment (P<0.05) of metabolic pathways in both strains, encompassing immune response, pathological indications, material metabolism, cellular processes, organic systems, environmental information processing, and genetic information processing. Among the pathways related to pathological indications, all DEGs were upregulated in only one out of 21 significant pathways for the symbiotic strain, while for the aposymbiotic strain, all DEGs were upregulated in 9 out of 14 significant pathways. This suggests a significantly higher activation level of pathological indicators in the aposymbiotic strain under PS NPs stress compared to the symbiotic strain, indicating a superior tolerance at the molecular level. In addition, all DEGs related to immune response in the aposymbiotic strain treated with PS NPs were upregulated, while only approximately half of the DEGs in the symbiotic strain were upregulated. This suggests a lower immune response sensibility to PS NPs in the symbiotic strain compared to the aposymbiotic strain. In summary, the difference in immune response sensibility to PS NPs between the two H. sinensis strains may underlie their differing tolerance to PS NPs stress at the molecular level. In addition, the symbiotic strain exhibits lower immune response sensitivity to PS NPs, possibly due to the host downregulating immune levels against foreign invaders to accommodate symbiotic algae. The study provides basic data for revealing the biotoxicity and molecular mechanism of nano-sized plastic particles.