Journal
ADVANCED HEALTHCARE MATERIALS
Volume 12, Issue 7, Pages -Publisher
WILEY
DOI: 10.1002/adhm.202202135
Keywords
cancer immunotherapy; diselenide prodrug; dual-responsiveness; pyroptosis
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Pyroptosis triggers antitumor immunity and this study introduces a dual-responsive diselenide-based pyroptosis inducer that has excellent tumor microenvironment targeting effects. It can remodel the immunostimulated tumor microenvironment and trigger a robust immune response. Combined with αPD-1 therapy, it effectively inhibits the growth of remote tumors and prolongs survival.
Pyroptosis is demonstrated to trigger antitumor immunity and represents a promising new strategy to potentiate cancer immunotherapy. The number of potent pyroptosis inducers, however, is limited and without tumor-targeting capability, which inevitably causes damage in normal tissues. Herein, a small molecular prodrug of paclitaxel-oxaliplatin is rationally synthesized, which can be covalently self-assembled with diselenide-containing cross-linking (Dse11), producing a diselenide nanoprodrug (DSe@POC) to induce pyroptosis for the first time. The diselenide bonds within DSe@POC can be split by high glutathione in the tumor microenvironment (TME) and reactive oxygen species induced by photodynamic therapy, thus possessing excellent TME on-target effects. Additionally, DSe@POC is able to elicit intense pyroptosis to remodel the immunostimulated TME and trigger a robust immune response. Furthermore, combined alpha PD-1 therapy effectively inhibits the growth of remote tumors through the abscopal effect, amplifies a long-term immune memory response to reject rechallenged tumors, and prolongs survival. Collectively, DSe@POC, as the first TME dual-responsive diselenide-based pyroptosis inducer, will open up an attractive approach for cancer immunotherapy.
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