A PROTAC Augmenter for Photo‐driven Pyroptosis in Breast Cancer

Abstract Proteolysis targeting chimera (PROTAC) has recently emerged as a promising strategy for inducing post‐translational knockdown of target proteins in disease treatment. The degradation of bromodomain‐containing protein 4 (BRD4), an essential nuclear protein for gene transcription, induced by PROTAC has been proposed as an epigenetic approach to treat breast cancer. However, the poor membrane permeability and indiscriminate distribution of PROTAC in vivo results in low bioavailability, limiting its development and application. Herein, we developed a nano “targeting chimera” (abbreviated as L@NBMZ) consisting of BRD4‐PROTAC combined with a photosensitizer, to serve as the first augmenter for photo‐driven pyroptosis in breast cancer. With excellent BRD4 degradation ability, high biosafety, and biocompatibility, L@NBMZ blocked gene transcription by degrading BRD4 through proteasomes in vivo, and surprisingly, induced the cleavage of caspase‐3. This type of caspase‐3 cleavage was synergistically amplified by light irradiation in the presence of photosensitizers, leading to efficient photo‐driven pyroptosis. Both in vitro and in vivo outcomes demonstrated the remarkable anti‐cancer efficacy of this augmenter, which significantly inhibitd the lung metastasis of breast cancer in vivo. Thus, the photo‐PROTAC “targeting chimera” augmenter construction strategy may pave a new way for expanding PROTAC applications within anti‐cancer paradigms. This article is protected by copyright. All rights reserved