Emerging Combinatorial Drug Delivery Strategies for Breast Cancer: A Comprehensive Review.

Breast cancer remains the second most prevalent cancer among women in the United States. Despite advancements in surgical, radiological, and chemotherapeutic techniques, multidrug resistance continues to pose significant challenges in effective treatment. Combination chemotherapy has emerged as a promising approach to address these limitations, allowing multiple drugs to target malignancies via distinct mechanisms of action. Increasingly, the use of phytoconstituents alongside chemotherapeutic agents has shown promise in enhancing treatment outcomes. This combination therapy acts on key signaling pathways such as Hedgehog, Notch, Wnt/β- catenin, tyrosine kinases, and phosphatidylinositol 3-kinase (PI3K), which play critical roles in cellular proliferation, apoptosis, angiogenesis, differentiation, invasion, and metastasis. This review explores various signaling pathways involved in breast cancer progression, discusses conventional treatment methods like surgery, adjuvant radiotherapy, hormonal therapy, and chemotherapy, and highlights emerging nanocarrier-based drug delivery systems (DDS). Liposomes, dendrimers, exosomes, polymeric micelles, and nanoparticles (organic, inorganic, gold, magnetic, carbon-based, and quantum dots) are examined as innovative strategies for enhancing drug delivery efficacy. Furthermore, stimuli-responsive DDSs, including reactive oxygen species (ROS), enzyme-, and hypoxia- responsive systems, are presented as cutting-edge approaches to overcoming drug resistance. Special emphasis is placed on the co-delivery of chemotherapeutic agents and plant-based compounds, particularly in estrogen receptor-positive (ER+) breast cancer. This review aims to provide a comprehensive overview of novel combinatorial strategies and advanced nanocarriers for the effective and targeted treatment of breast cancer.