Nanoparticle‐Mediated TIPE1 mRNA Delivery Enhances Paclitaxel Sensitivity in Triple‐Negative Breast Cancer by Modulating RAB7A Ubiquitination‐Associated Stability and Autophagy

Abstract

ABSTRACT Acquired paclitaxel (PTX) resistance remains a major obstacle in triple‐negative breast cancer (TNBC) treatment. This study investigated TIPE1's role in regulating autophagy and PTX sensitivity and developed ROS‐responsive TIPE1 mRNA‐loaded nanoparticles (TIPE1m NPs) as a therapeutic strategy. PTX‐resistant TNBC cell lines were established, and integrated transcriptomic and proteomic analyses were performed. TIPE1 was downregulated in resistant cells, while higher TNFAIP8L1 expression in public breast cancer cohorts was associated with better survival and improved PTX response. Mechanistically, TIPE1 overexpression was associated with ubiquitination‐related reduction in the stability of the small GTPase RAB7A, leading to impaired autophagic flux, increased ROS accumulation, and enhanced PTX‐induced apoptosis. Conversely, TIPE1 knockdown stabilized RAB7A, enhanced autophagy, and increased PTX tolerance. ROS‐responsive TIPE1m NPs were constructed to restore TIPE1 expression in resistant cells. TIPE1m NPs suppressed autophagy, increased ROS, and enhanced PTX‐induced apoptosis in vitro. In PTX‐resistant xenografts, combined TIPE1m NPs and PTX treatment suppressed tumor growth without obvious systemic toxicity. These findings identify the TIPE1–RAB7A–autophagy axis as a potential therapeutic target and support TIPE1 mRNA delivery as a strategy to overcome PTX resistance in TNBC.