Multiple therapeutic mechanisms of pyrrolic N-rich g-C₃N₄ nanosheets with enzyme-like function in the tumor...

Nanozyme-based synergistic catalytic therapies for tumors have attracted extensive research attention. However, the unsatisfactory efficiency and negative impact of the tumor microenvironment (TME) hinder its clinical applications. In this study, we provide an easy method to prepare transition metals loaded onto pyrrolic nitrogen-rich g-C₃N₄ (PN-g-C₃N₄) for forming metal-N4 sites. This N-rich material effectively transfers electrons from g-C₃N₄ to metal-N4 sites, promotes the oxidation-reduction reaction of metals with different valence states, and improves material reusability. Under TME conditions, copper ions loaded onto PN-g-C₃N₄ (Cu-PN-g-C₃N₄, CPC) can produce ·OH through a Fenton-like reaction for tumor inhibition. This Fenton-like reaction and tumor cell inhibition can be improved further by a photodynamic effect caused by light irradiation. We introduced upconversion nanoparticles (UCNPs) into CPC to obtain nano-enzymes (UCNPs@Cu-PN-g-C₃N₄, UCPC) for effectively penetrating the tissue, which emits light corresponding to the UV absorption region of CPC when excited with 980 nm near-infrared (NIR) light. The nanoplatform can reduce H₂O₂ concentration upon exposure to NIR light; this induces an increase in dissolved oxygen content and produces a higher supply of reactive oxygen species (ROS) for destroying tumor cells. Owing to the narrow bandgap (1.92 eV) of UCPC under 980 light irradiation, even under the condition of hypoxia, the excited electrons in the conduction band can reduce insoluble O₂ through a single electron transfer process, thus effectively generating O₂^•-. Nanoenzyme materials with catalase properties produce three types of ROS (·OH, O₂^•- and ¹O₂) when realizing chemodynamic and photodynamic therapies. An excellent therapeutic effect was established by killing cells in vitro and the tumor-inhibiting effect in vivo, proving that the prepared nanoenzymes have an effective therapeutic effect and that the endogenous synergistic treatment of multiple treatment technologies can be realized.