Manganese-doping titanium disulfide cascade nanobioreactors for sequential gas-sonodynamic strategy with immune checkpoint blockade therapy of cancer

Sonodynamic therapy (SDT)-induced immunogenic cell death (ICD) features the potential for cancer therapy. However, SDT alone is weak to trigger robust ICD. Herein, PEGylation manganese-doping titanium disulfide nanosheets (PEG-Mn: TiSx NSs, abbreviated as MnTiS-PEG) are fabricated as a kind of cascade bioreactor for sequential gas therapy (GT)-enhanced SDT. MnTiS-PEG could release H₂S gas to first induce cell apoptosis via mitochondria damage, accompanied by an oxidative degradation that would boost the efficacy of the sonodynamic effects under US irradiation, which is much superior to the commercial TiO₂. With Mn²⁺ releasing, such cascade process could further trigger satisfactory ICD and enhance dendric cells (DCs) maturation. In vitro and in vivo results illustrate the outstanding outcomes of such sequential GT-SDT along with a series of immune responses. Considering the possible immune tolerance, anti-programmed cell death-1 (αPD-L1), an immune checkpoint inhibitor, is employed subsequently to further inhibit tumor growth. It is found that this combination displays not only an excellent therapeutical performance on the primary tumors, but also an abscopal effect at the same time. Briefly, our work establishes a cascade bioreactor for the programmed GT-SDT with satisfactory immune responses, which provides an effective method for enhancing SDT and immunotherapy.