Oxygen self-supplying perfluorocarbon-functionalized ferrocene nanosheets for enhanced cancer chemodynamic therapy

Ferrocene, known for its 'sandwich' structure and Fenton catalytic activity for tumor treatment, its two-dimensional (2D) self-assembly has not yet been exploited for therapeutic applications. Perfluorocarbons (PFCs) can carry and transport oxygen to alleviate tumor hypoxia. Nevertheless, designing ferrocene derivatives with PFC chains to alleviate tumor hypoxia and improve cancer treatment remains a challenge. Here, we first synthesized ferrocene derivatives with different PFC chains (nF-Fc, n = 5, 9, 13) by conjugating perfluorocarbonic acids with 2-(ferrocenylethynyl)aniline (Fc). These derivatives were able to self-assemble into 2D nanosheets, with hydrated particle size decreasing as the chain length increased. The chain lengths also influenced the oxygen-carrying capacity, iron release capacity, and glutathione consumption capacity, all of which impacted their ability to alleviate tumor hypoxia, produce intracellular reactive oxygen species, and enhance chemodynamic therapeutic efficacy. Notably, PFC incorporation altered the mechanism of induced cell death. By elucidating the effects of ferrocene derivatives with different PFC chains on the hypoxic tumor microenvironment (TME) and their therapeutic efficacy, this research advances the development of ferrocene-based 2D materials for cancer treatment and offers a novel approach to optimize compound structures better regulation of the hypoxic TME, ultimately improving therapeutic outcomes.