Nano-enabled delivery of natural products and combinatorial chemotherapy for triple-negative breast cancers: mechanisms, synergy, and translational challenges

Among breast cancer subtypes, Triple-negative breast cancer (TNBC) is recognized for its aggressive behavior and is characterized by the absence of hormone receptors (estrogen and progesterone) and HER2 overexpression. This absence results in fewer treatment options and less favorable health outcomes. Conventional chemotherapy remains the standard treatment; however, its systemic toxicity and adverse effects emphasize the necessity for improved and safer alternatives. In this context, exploring naturally derived compounds from the plant kingdom for their promising therapeutic activities is a current trend, as they can induce apoptosis, modulate key signaling pathways, and enhance anti-tumor effects and immune responses through single or multiple mechanisms. Although they have potential, clinical use is limited by challenges such as poor solubility, instability, and low bioavailability, which can be overcome with nanocarrier delivery systems. This review discusses insightful advances in nano-enabled combinatorial therapy for TNBC, focusing on the co-delivery of phytochemicals, extracts, and essential oils alongside conventional chemotherapeutics. Importantly, we critically evaluate current methodologies for assessing drug synergism, including the Chou–Talalay, Bliss independence, and Loewe additivity models, and highlight the lack of standardized application across studies. Furthermore, we address key translational challenges, including formulation complexity, pharmacokinetic incompatibility, and insufficient toxicity evaluation, while briefly outlining emerging computational perspectives, such as multi-omics for future combination design. This review offers a helpful framework by combining nanotechnology, natural product pharmacology, and synergy assessment to guide next-generation combination therapies for TNBC. Nano-enabled co-delivery systems boost the effectiveness of combined chemotherapy and natural products in TNBC. Nanocarriers enable co-loading of hydrophilic and hydrophobic drugs, enhancing stability and bioavailability. Combinatorial strategies target resistance, cancer stem cells, and signaling in TNBC. Translational challenges, including formulation complexity and toxicity assessment, remain critical barriers to clinical application.