circRNA03358-directed metabolic reprogramming confers Physarum flavicomum GD217 with specific resistance to TiO2 nanoparticles: Moving toward the path of combating nanoparticle pollution/exposure.

The increasing use of titanium dioxide (TiO2) nanoparticles (NPs) has raised concerns related to their environmental accumulation and the associated ecological risks. Understanding the key biomolecular responses of TiO₂ NP-tolerant organisms like Physarum flavicomum GD217 is essential for combating the pollution of and exposure to these NPs. In this study, we employed multi-omics approaches combined with molecular biology techniques to investigate the stress responses of GD217 to mixed-phase TiO₂ NPs (M-TiO₂ NPs). We found that GD217's response is primarily metabolism-related and identified circular RNA 03358 (circRNA03358) as a key regulator through competitive endogenous RNA networks. This circRNA drives efficient metabolic reprogramming, conferring specific resistance to TiO₂ NPs. On the basis of these insights, we designed mitigation schemes using circRNA03358 and related metabolites that significantly enhanced tolerance in non-resistant cells, including human Caco-2 cells, Crucian carp intestinal epithelial cells, Pichia spp., and other Physarum strains, against M-TiO₂ NPs of varying particle sizes under both light and dark conditions. Furthermore, these metabolite-based schemes effectively mitigated cell damage in mouse subcutaneous cells collected from suspected TiO₂ NP-contaminated areas. In summary, our study identifies important biomolecules (circRNA03358 and related metabolites) that enhance cellular resistance to TiO₂ NPs, advances understanding of microbial stress responses, and provides novel insights and strategies for combating TiO₂ NP pollution/exposure.