An ultrasound-activated PROTAC prodrug with self-reporting fluorescence for targeted protein degradation.

PROteolysis TArgeting Chimeras (PROTACs) have emerged as a pharmacological tool for selectively degrading disease-associated proteins of interest (POIs). However, PROTACs-mediated protein degradation often lacks precise spatiotemporal control, potentially disrupting protein homeostasis in normal tissues and causing physiological toxicity. To address these challenges, we developed an ultrasound-activated PROTAC prodrug platform (US-PROTAC) that enables spatiotemporally controlled PROTAC activation with non-invasive, in situ fluorescence-guided monitoring. This platform consists of three essential components: a near-infrared fluorescent reporter (methylene blue, MB) for bioimaging feedback, a PROTAC molecule selectively targeting POIs, and a self-immolative linker for ultrasound-triggered activation. The protein degradation activity of US-PROTAC is masked under physiological conditions. However, ultrasonic stimulation generates hydroxyl radicals (•OH) through cavitation dynamics, selectively cleaving urea bonds and restoring MB fluorescence. This process simultaneously triggers a self-immolative reaction that releases active PROTAC. Importantly, MB fluorescence recovery enables real-time visualization of ultrasound-triggered PROTAC release in vitro and in vivo. The combination of ultrasound-mediated activation and fluorescence imaging further enables modulation of therapeutic efficacy by adjusting ultrasound parameters, offering a practical tool for optimizing spatiotemporal control of targeted protein degradation.

• Publication year

  2026

• Venue

  Biomaterials

• Publication date

  2026-02-02

• Fields of study

  Medicine, Engineering

• Identifiers
  DOI 10.1016/j.biomaterials.2026.124045PMID 41643569
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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