CYP450 activation and mitophagy induction mediate Ti₃C₂ MXene detoxification in RAW 264.7 cells

The rapid expansion of engineered nanoparticle applications has raised critical environmental and health concerns. While traditional toxicological studies have focused primarily on nanoparticle-induced cytotoxicity, they often overlook dynamic cellular defense responses. Here, we elucidate the detoxification strategies employed by macrophages to process MXenes-emerging two-dimensional transition metal carbides and nitrides with exceptional conductivity and biocompatibility but susceptibility to oxidative degradation, revealing a bipartite mechanism that converts material instability into a functional cellular detoxification pathway. Using RAW 264.7 cells, we show that Ti₃C₂ MXene undergoes accelerated intracellular oxidation compared to cell culture medium, driving its detoxification. This process is mediated by MXene-induced activation of CYP450 enzymes and generation of reactive oxygen species, which collectively metabolize and degrade pristine MXene into less toxic oxidized derivatives, constituting the primary cellular defense mechanism. Residual oxidative damage further triggers mitochondrial depolarization, initiating PINK1/Parkin-dependent mitophagy to eliminate dysfunctional organelles and restore homeostasis. Our findings redefine MXene biological interactions, demonstrating that rapid oxidation is not just a material limitation but a critical detoxification trigger. This paradigm shift provides a new framework for designing safer next-generation 2D materials, though the long-term physiological costs of sustained pathway activation remain a critical area for future investigation.