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FR-05

Sono-PROTAC strategy: Engineered phosphorus nanosheets as a dual

sonodynamic and nano-PROTAC platform for cancer therapy

1,2
,1
Wei-Chieh Liu, Wei Chen*

1 Genomics Research Center, Academia Sinica, Taipei, Taiwan
* E-mail: wchen123@as.edu.tw (W.C.)

Abstract
Ultrasound (US)-mediated sonodynamic therapy (SDT) has gained considerable attention as
a promising, non-invasive approach to cancer treatment due to its deep tissue penetration
capabilities. Despite its potential, significant challenges remain in designing biocompatible
nanomaterials with efficient SDT activity. In this study, we developed engineered phosphorus
nanosheets (EPNs) as an innovative sonosensitizer. These EPNs possess a narrow bandgap,
narrower than most conventional nano-sonosensitizers, which facilitates a more efficient US-
triggered separation of electron-hole pairs, thereby enhancing the generation of reactive oxygen
species (ROS) for anti-tumor efficacy. To further sensitize tumor cells to SDT, we explored the
potential of EPNs as carriers for PROteolysis TArgeting Chimeras (PROTACs), a novel drug
technology primarily designed for targeted protein degradation, which highly impacts the
pathway we are targeting. We demonstrate that this strategy plays a crucial role in antioxidant
defense within 4T1 cancer cells, thereby making them more susceptible to ROS produced by
US activation and augment anti-tumor therapeutic efficacy. Collectively, this study introduces
an innovative strategy that synergistically enhances SDT and antitumor Nano-PROTAC
technology; this combined US-mediated sono-PROTAC strategy offers a promising therapeutic
pathway for advancing cancer nanomedicine.

Keywords: Anticancer treatment; Sonodynamic therapy; PROTAC; Phosphorus nanosheets