Devising Biocompatible, NIR‐Activated Helical Pyroptosis Agents via 𝛑‐Twisting Strategy for Promoting Antitumor Immunity

Abstract Specifically controlling cell pyroptosis is advantageous for oncotherapy as it allows simultaneous ablation of primary tumors and activation of immunogenicity of tumor environment. Herein, a facile and robust strategy is presented to construct efficient NIR‐activated helical pyroptosis agents (PyroAs) with negligible dark cytotoxicity. It is demonstrated that the construction of four intramolecular B‐X bonds (X = O or N) within the BODIPY chromophore enforces a significant twisting of its π‐conjugation, yielding a variety of helical H BD molecules with desired high photosensitivity and negligible dark toxicity. A robust approach is established to extend H BD into the near‐infrared (NIR) region through site‐selective incorporation of an electron‐withdrawing ester moiety. It is also proved that targeted delivery of the NIR‐activated H BD‐ER to the endoplasmic reticulum (ER) specifically activates pyroptosis pathway by equipping it with an ER‐targeting moiety. Finally, the favorable biocompatibility, excellent antitumor efficacy, and remarkable systematic immune response of this unique NIR‐activated helical PyroAs are shown in vivo, demonstrating its potential application in solid tumor immunotherapy.