1. A photoactivatable upconverting nanodevice boosts the lysosomal escape of PROTAC degraders for enhanced combination therapy.
- Author
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Zhan J, Li X, Mu Y, Yao H, Zhu JJ, and Zhang J
- Subjects
- Humans, Animals, Transcription Factors metabolism, Transcription Factors antagonists & inhibitors, Transcription Factors chemistry, Mice, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins metabolism, Infrared Rays, Rose Bengal chemistry, Rose Bengal pharmacology, Rose Bengal administration & dosage, Silicon Dioxide chemistry, Polylysine chemistry, Reactive Oxygen Species metabolism, Cell Line, Tumor, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents administration & dosage, Bromodomain Containing Proteins, Lysosomes metabolism, Nanoparticles chemistry, Nanoparticles administration & dosage, Photosensitizing Agents chemistry, Photosensitizing Agents pharmacology, Photosensitizing Agents administration & dosage, Proteolysis drug effects, Photochemotherapy
- 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.
- Published
- 2024
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