Nanozymes subvert pharmacological conventions: insights from counteracting the placental side effects of TiO₂ nanozymes.

As a classic nanozyme, titanium dioxide (TiO₂) is increasingly utilized in medical fields such as anti-infection, tumor therapy, and inflammation regulation. However, their expanding application has raised concerns regarding biosafety, particularly their potential threat to maternal and fetal health. To evaluate this risk, this study established a pregnant rat model, focusing on the placenta as a potential target organ, to investigate the developmental toxicity and potential interventions associated with the use of TiO₂ nanozymes (TiO₂ NZs) as therapeutic agents during pregnancy. The results revealed that gestational intake of TiO₂ NZs led to fetal growth restriction, abnormal placental weight increase, and induced placental energy metabolism disruption along with excessive autophagy activation. Surprisingly, when attempting to reverse these toxic effects, we found that TiO₂ NZs suppressed AMPK expression, prompting Compound C and phenformin to unconventionally regulate energy imbalance-induced autophagy via non-AMPK/mTOR pathway-dependent mechanisms. This resulted in a complex scenario where the two drugs produced inverted effects-"aggravation" vs. "alleviation"-during intervention. These findings indicate that despite the significant medical value of TiO₂ as a nanozyme, they pose non-negligible safety risks, and pharmacological interventions may trigger unexpected effects. Therefore, while advancing their clinical application, it is crucial to prioritize in-depth mechanistic studies and the development of precise intervention strategies, especially ensuring the long-term health and safety for maternal and fetal populations.