Overcoming Chemotherapy Resistance in Triple-Negative Breast Cancer with Nanocarrier-Delivered siRNA Therapeutics

TL;DR

This paper reviews how nanocarriers delivering siRNA can overcome chemotherapy resistance in triple-negative breast cancer by targeting resistance mechanisms and improving treatment outcomes.

Contribution

The paper provides a comprehensive review of nanocarrier-based siRNA delivery systems for reversing drug resistance in TNBC.

Findings

Nanocarriers can protect siRNA, enhance tumor accumulation, and enable targeted intracellular release.

siRNA-loaded nanocarriers reverse drug resistance mechanisms and improve antitumor responses in resistant TNBC models.

Several platforms reduced metastatic spread and improved survival in preclinical studies.

Abstract

Triple-negative breast cancer (TNBC) represents 10–20% of breast cancers and is characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, leaving cytotoxic chemotherapy as the main systemic treatment. However, rapid development of resistance, via drug efflux, enhanced DNA repair, apoptosis evasion, epithelial-to-mesenchymal transition, and tumor microenvironment protection, limit long-term efficacy. Small interfering RNA (siRNA) therapeutics can silence key resistance drivers, but their clinical potential is hindered by instability, poor biodistribution, and off-target effects. Nanocarrier-based delivery systems offer solutions by protecting siRNA, enhancing tumor accumulation, enabling targeted intracellular release, and permitting co-delivery with chemotherapeutics for synergistic effects. We conducted a narrative review in PubMed from database inception to August 2025. The included studies demonstrated that lipid, polymeric, inorganic, and hybrid nanocarriers can achieve efficient target knockdown, reverse drug resistance mechanisms, and significantly enhance antitumor responses in resistant TNBC models. Several platforms also reduced metastatic spread and improved survival in vivo. While preclinical results are compelling, clinical translation remains limited by incomplete safety profiling and heterogeneity in delivery efficiency. This review synthesizes mechanistic insights and delivery innovations, outlining a roadmap for translating siRNA-loaded nanocarriers into effective therapies for chemoresistant TNBC.

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