Nanomedicine-enabled delivery of natural products targeting the Notch cascade: addressing translational barriers in cancer therapy
Abstract
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.
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BibTeX
@article{shi2026nanomedicineenabled,
title = {{Nanomedicine-enabled delivery of natural products targeting the Notch cascade: addressing translational barriers in cancer therapy}},
author = {Qingmiao Shi and Zhibo Zhang and Xiaonan Geng and Yixin Kang},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.2022548},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.2022548},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Nanomedicine-enabled delivery of natural products targeting the Notch cascade: addressing translational barriers in cancer therapy
AU - Qingmiao Shi
AU - Zhibo Zhang
AU - Xiaonan Geng
AU - Yixin Kang
PY - 2026
DA - 2026/11/09
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.2022548
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.2022548
AB - 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.
SN - 1663-9812
ER -