Abstract：
PROteolysis TArgeting Chimeras have received increasing attention due to their capability to induce potent degradation of various disease-related proteins. However, the effective and controlled cytosolic delivery of current small-molecule PROTACs remains a challenge, primarily due to their intrinsic shortcomings, including unfavorable solubility, poor cell permeability, and limited spatiotemporal precision. Here, we develop a near-infrared light-controlled PROTAC delivery device (abbreviated as USDPR) that allows the efficient photoactivation of PROTAC function to achieve enhanced protein degradation. The nanodevice is constructed by encapsulating the commercial BRD4-targeting PROTACs (dBET6) in the hollow cavity of mesoporous silica-coated upconversion nanoparticles, followed by coating a Rose Bengal (RB) photosensitizer conjugated poly-L-lysine (PLL-RB). This composition enables NIR light-activatable generation of cytotoxic reactive oxygen species due to the energy transfer from the UCNPs to PLL-RB, which boosts the endo/lysosomal escape and subsequent cytosolic release of dBET6. We demonstrate that USDPR is capable of effectively degrading BRD4 in a NIR light-controlled manner. This in combination with NIR light-triggered photodynamic therapy enables an enhanced antitumor effect both in vitro and in vivo. This work thus presents a versatile strategy for controlled release of PROTACs and codelivery with photosensitizers using an NIR-responsive nanodevice, providing important insight into the design of effective PROTAC-based combination therapy.
摘要：
由于它们能够诱导各种疾病相关蛋白的有效降解，蛋白质分解的衔接嵌合体受到了越来越多的关注。然而,当前小分子PROTACs的有效和受控的胞浆递送仍然是一个挑战，主要是由于它们的内在缺点，包括不利的溶解度，细胞渗透性差，和有限的时空精度。这里,我们开发了一种近红外光控制的PROTAC递送装置（缩写为USDPR），该装置允许PROTAC功能的有效光活化以实现增强的蛋白质降解。通过将商业BRD4靶向PROTACs（dBET6）封装在介孔二氧化硅包覆的上转换纳米颗粒的空腔中来构建纳米器件，然后涂覆玫瑰红(RB)光敏剂缀合的聚-L-赖氨酸(PLL-RB)。由于从UCNP到PLL-RB的能量转移，该组合物能够实现细胞毒性活性氧的NIR光活化生成。这促进了内/溶酶体逃逸和随后的dBET6的胞浆释放。我们证明USDPR能够以NIR光控制的方式有效地降解BRD4。这与NIR光触发的光动力疗法组合能够在体外和体内增强抗肿瘤作用。因此，这项工作提出了一种使用NIR响应型纳米器件控制PROTACs释放和与光敏剂共同递送的通用策略。为设计基于PROTAC的有效联合疗法提供重要见解。
