A PROTAC Augmenter for Photo‐Driven Pyroptosis in Breast Cancer

上睑下垂 材料科学 乳腺癌 纳米技术 癌症 医学 内科学 炎症体 炎症
作者
Daipeng Huang,Yang Zou,Haiqiao Huang,Jikai Yin,Saran Long,Wen Sun,Jianjun Du,Jiangli Fan,Xiaoqiang Chen,Xiaojun Peng
出处
期刊:Advanced Materials [Wiley]
卷期号:36 (21) 被引量:4
标识
DOI:10.1002/adma.202313460
摘要

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 is 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, 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, is developed. With excellent BRD4 degradation ability, high biosafety, and biocompatibility, L@NBMZ blocks gene transcription by degrading BRD4 through proteasomes in vivo, and surprisingly, induces the cleavage of caspase-3. This type of caspase-3 cleavage is synergistically amplified by light irradiation in the presence of photosensitizers, leading to efficient photo-driven pyroptosis. Both in vitro and in vivo outcomes demonstrate the remarkable anti-cancer efficacy of this augmenter, which significantly inhibits 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.
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