Nanoparticle-Mediated TIPE1 mRNA Delivery Enhances Paclitaxel Sensitivity in Triple-Negative Breast Cancer by...

Area of Science:

• Oncology
• Molecular Biology
• Nanomedicine

Background:

• Acquired paclitaxel (PTX) resistance is a significant challenge in treating triple-negative breast cancer (TNBC).
• Autophagy dysregulation and reactive oxygen species (ROS) accumulation contribute to PTX resistance in TNBC.
• The role of TIPE1 in PTX resistance and autophagy in TNBC requires further elucidation.

Purpose of the Study:

• To investigate the role of TIPE1 in regulating autophagy and PTX sensitivity in TNBC.
• To develop ROS-responsive TIPE1 mRNA-loaded nanoparticles (TIPE1m NPs) to overcome PTX resistance.
• To explore the therapeutic potential of TIPE1 mRNA delivery in combination with PTX for TNBC treatment.

Main Methods:

• Establishment of PTX-resistant TNBC cell lines.
• Integrated transcriptomic and proteomic analyses.
• Construction and in vitro/in vivo evaluation of ROS-responsive TIPE1m NPs.
• Assessment of autophagy flux, ROS levels, apoptosis, and tumor growth.

Main Results:

• TIPE1 was downregulated in PTX-resistant TNBC cells, while TNFAIP8L1 expression correlated with better survival and PTX response.
• TIPE1 overexpression reduced RAB7A stability, impaired autophagic flux, increased ROS, and enhanced PTX-induced apoptosis.
• TIPE1 knockdown stabilized RAB7A, promoted autophagy, and increased PTX tolerance.
• TIPE1m NPs restored TIPE1 expression, suppressed autophagy, increased ROS, and enhanced PTX-induced apoptosis in vitro and in vivo.
• Combined TIPE1m NPs and PTX treatment suppressed tumor growth in PTX-resistant xenografts with minimal toxicity.

Conclusions:

• The TIPE1-RAB7A-autophagy axis is a critical regulator of PTX resistance in TNBC.
• TIPE1 mRNA delivery via ROS-responsive nanoparticles is a promising strategy to overcome PTX resistance in TNBC.
• Targeting TIPE1 offers a potential therapeutic avenue for improving PTX efficacy in resistant TNBC.