Nanotechnology strategies to enhance berberine efficacy in triple-negative breast cancer through delivery platforms and clinical translation challenges

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It remains difficult to treat because of its heterogeneity, metastatic potential, and resistance to therapy. Berberine exhibits promising anticancer activity. However, pharmacokinetic and delivery limitations, including poor solubility, low bioavailability, rapid metabolism, and inadequate tumor targeting, may limit its clinical translation. To critically review molecular mechanisms of berberine nano-based delivery strategies, translational challenges, and future perspectives for TNBC treatment. PubMed, Scopus, Web of Science, and Google Scholar searches were performed to identify relevant published studies. This narrative review followed the Scale for the Assessment of Narrative Review Articles (SANRA) framework. The findings from preclinical studies were qualitatively synthesized and critically appraised. This review showed that berberine suppresses TNBC progression by modulating multiple signaling pathways, including PI3K/AKT/mTOR, EGFR/MEK/ERK, NF-κB, STAT3, AMPK, TGF-β, Wnt/β-catenin, and NLRP3. Nanoformulations, including polymeric nanoparticles, lipid-based nanocarriers, dendrimers, micelles, inorganic, hybrid, and stimuli-responsive systems, improved solubility, bioavailability, stability, tumor accumulation, and intracellular delivery. These improvements enhanced therapeutic efficacy. Polymeric and lipid-based nanocarriers demonstrated the greatest translational potential because of their favorable efficacy, biocompatibility, and scalability. However, clinical translation remains limited by insufficient human evidence, safety concerns, manufacturing complexity, regulatory uncertainty, and lack of standardized formulations. Nano-berberine represents a promising strategy for TNBC treatment. Clinical translation will require standardized formulations, safety assessments, scalable production, regulatory alignment, and well-designed clinical trials.