Targeting the transferrin receptor in breast cancer: nanotechnology-based drug delivery strategies

Breast cancer remains a leading cause of cancer-related morbidity and mortality worldwide, with treatment efficacy often limited by systemic toxicity, poor tumor selectivity, and multidrug resistance. Nanotechnology-based drug delivery systems offer a promising strategy to enhance therapeutic precision, particularly through active targeting of tumor-associated receptors. The transferrin receptor (TfR), which is frequently overexpressed in breast cancer cells, has emerged as an attractive target due to its role in receptor-mediated endocytosis. This review critically summarizes recent advances in transferrin-functionalized nanocarriers for breast cancer therapy, including liposomal, polymeric, dendrimeric, metallic, and hybrid platforms. Key design parameters influencing cellular uptake, biodistribution, and therapeutic efficacy - such as particle size, surface charge, ligand density, and release behavior - are discussed. We highlight progress in multifunctional and stimuli-responsive systems designed to overcome tumor microenvironment barriers and multidrug resistance. In addition, emerging evidence on the role of the gut microbiota in modulating breast cancer progression and treatment response is examined, with a focus on its potential impact on targeted nanomedicine efficacy. Finally, current translational challenges and future directions, including personalized and microbiome-informed nanotherapeutic strategies, are outlined. Literature was identified through systematic searches of PubMed, Web of Science, Scopus, and Google Scholar from January 2005 to March 2025.