Broken but not beaten: Unraveling the biotransformation fate of Mn@PCN224 nanozymes and its influence on enzymatic activity and safety at the human placenta in vitro

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Chronic placental inflammation has been associated with severe pregnancy complications including miscarriage, stillbirth, premature delivery, intra-uterine growth restriction, and recurrence risk in future pregnancies. Treatments are essential, but current standard therapies for infections and inflammation often struggle with limited efficacy and potential side effects. Nanomaterials with enzyme-mimetic properties (nanozymes) have demonstrated impressive medical capabilities especially in inflammation treatment. Remarkably, single-atom nanozymes (SAzymes) including metal-organic frameworks (MOFs) have attracted considerable attention due to their superior substrate affinity and catalytic activity compared to conventional nanozymes. However, due to their high reactivity, nanozymes could undergo biotransformation in biological fluids and tissues, affecting their physicochemical properties and potentially compromising their therapeutic efficacy and safety. On this basis, we performed a systematic study on the chemical and structural biotransformation, catalytic activity and biological impact of a PCN224 MOF at the human placenta in vitro . We engineered a PCN224 MOF, composed of zirconium clusters (Zr 6 ) and 4-carboxyphenyl-porphyrin (H 2 TCPP), further doping it with Mn (Mn@PCN224) to form Mn-TCPP complexes. These complexes mimic the natural Mn-superoxide dismutase (MnSOD), a crucial enzyme to detoxify cells from radical stress during inflammation. In biological media, Mn@PCN224 underwent rapid and substantial decomposition, leading to a significant release of Mn-TCPP complexes. Nonetheless, despite the observed biotransformation, the SOD activity was maintained, mostly by the free Mn-TCPP bearing the enzyme-like active center. We further revealed that Mn@PCN224 SAzymes and their biotransformation products did not compromise cell viability, barrier integrity and endocrine function in an in vitro human placenta co-culture model. The current findings provide crucial insights about the biotransformation mechanism of a MOF-based SAzyme and emphasize the importance of biostability assessment, in addition to efficacy and safety evaluation.

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