Proton pump inhibitor-enhanced nanocatalytic ferroptosis induction for stimuli-responsive dual-modal molecular imaging guided cancer radiosensitization

Although radiotherapeutic efficiency has been revealed to be positively correlated with ferroptosis, the neutral/alkaline cytoplasm pH value of tumor cells remains an intrinsic challenge for efficient Fenton/Fenton-like reaction-based ferroptosis induction. Herein, PEGylated hollow mesoporous organosilica nanotheranostics (HMON)-GOx@MnO₂ nanoparticles (HGMP NPs) were designed as a ferroptosis inducer, which could specifically release Mn²⁺ in tumor cells to activate the Fenton-like reaction for ferroptosis induction. Proton pump inhibitors (PPIs) were synchronously administered for cytoplasm pH level regulation by inhibiting V-H⁺-ATPases activity, enhancing Fenton-like reaction-based ferroptosis induction. Moreover, reactive oxygen species production was facilitated via the glucose oxidase triggered cascade catalytic reaction by utilizing intracellular β-D-glucose for H₂O₂ self-supply and generation of additional cytoplasm H⁺. The PPI enhanced ferroptosis inducing nanosystem effectively inhibited tumor growth both in vitro and in vivo for tumor-specific ferroptosis induction and radiotherapy sensitization, suggesting that PPI administration could be an efficient adjuvant to reinforce Fenton/Fenton-like reaction-based ferroptosis induction for radiosensitization. STATEMENT OF SIGNIFICANCE: The cytoplasm pH value of tumor cells is typically neutral to alkaline, which is higher than that of the Fenton/Fenton-like reaction desired acidic environments, hindering its efficiency. In this study, PEGylated hollow mesoporous organosilica nanotheranostics (HMON)-GOx@MnO₂ nanoparticles were synthesized as a ferroptosis inducer, which could specifically release Mn²⁺ via depleting glutathione and then activate the Fenton-like reaction in the tumor microenvironment. The glucose oxidase was applied for H₂O₂ self-supply and addition of cytoplasm H⁺ to further boost the Fenton-like reaction. We found that proton pump inhibitors (PPIs) increased intracellular acidification by inhibiting the activity of V-H⁺-ATPases to enhance the Fenton reaction-based ferroptosis induction, suggesting PPIs administration could be a feasible strategy to reinforce ferroptosis induction for radiosensitization.