Ultrasound-responsive nanodroplets activate the Hippo pathway via ROS-MST1-YAP cascade for breast cancer therapy

Area of Science:

• Oncology
• Nanotechnology
• Biomedical Engineering

Background:

• Dysregulated Hippo signaling drives cancer proliferation, invasion, and metastasis.
• Targeted modulation of the Hippo pathway is a significant challenge in cancer therapy.

Purpose of the Study:

• To develop an albumin-based, ultrasound-responsive nanodroplet (FLU-ND) system for targeted Hippo pathway reprogramming.
• To investigate the efficacy of FLU-NDs in suppressing tumor growth and metastasis.

Main Methods:

• Encapsulation of fluvastatin (FLU) into albumin-based nanodroplets (FLU-NDs).
• Utilizing dual-delivery strategy: albumin-mediated enrichment and ultrasound-triggered release.
• Investigating the mechanism involving reactive oxygen species (ROS)-mammalian sterile 20-like kinase 1 (MST1)-yes-associated protein (YAP) axis via ultrasound-targeted microbubble destruction (UTMD).

Main Results:

• FLU-NDs demonstrated efficient drug loading, biocompatibility, and enhanced ultrasound imaging.
• Dual-delivery strategy achieved significant tumor accumulation and precise drug release.
• Synergistic Hippo pathway modulation via UTMD and FLU-NDs was observed, activating MST1 and inhibiting YAP.
• Significant tumor apoptosis, EMT reversal, and inhibition of tumor growth and metastasis in vitro and in vivo.

Conclusions:

• Established a novel theranostic platform using FLU-NDs for precise Hippo-targeted cancer therapy.
• Demonstrated high efficacy and low toxicity for tumor suppression and metastasis inhibition.
• Highlighted a new strategy for Hippo pathway modulation through UTMD-associated mechanisms.