Nanomedicine-enabled delivery of natural products targeting the Notch cascade: addressing translational barriers in cancer therapy

Notch signaling is a conserved cell-fate pathway that becomes therapeutically important when malignant cells use it to sustain stemness, epithelial plasticity, vascular remodeling, immune escape, and resistance to cytotoxic therapy. Natural products provide a chemically diverse source of Notch modulators, including polyphenols, flavonoids, alkaloids, terpenoids, and related phytochemicals that can influence receptor activation, nuclear Notch signaling, and downstream phenotypes. Their multi-target behavior is attractive in heterogeneous tumors, yet the same compounds often suffer from poor aqueous solubility, rapid metabolism, low systemic exposure, weak tumor accumulation, and formulation instability. Nanomedicine offers a practical route to re-engineer these compounds as therapeutic systems rather than isolated small molecules. Liposomes, polymeric nanoparticles, solid lipid systems, hydrogels, biomimetic carriers, and stimulus-responsive platforms can increase bioavailability, prolong circulation, improve tumor localization, and support co-delivery with chemotherapy, nucleic acids, immunomodulators, or pathway inhibitors. This review summarizes the Notch cascade in cancer, representative natural products that modulate Notch-driven cancer phenotypes, pharmacokinetic barriers that restrict their translation, and nanomedicine strategies that may overcome these barriers. It also discusses active targeting of the Notch/cancer stem cell axis, biomimetic delivery, co-delivery systems for resistance reversal, and translational challenges involving nanotoxicity, manufacturing, advanced models, and systems-level evaluation.