Mechanistic insights and nanomedicine innovations of oligomeric proanthocyanidin in precision oncology: Ablating self-renewal capacity of metastatic cancer stem cells via multi-pathway modulation.

Oligomeric proanthocyanidins (OPCs), condensed tannins found plentiful in grape seeds and berries, have higher bioavailability and therapeutic benefits due to their low degree of polymerization. Recent evidence places OPCs as effective modulators of cancer stem cell (CSC) plasticity and tumor growth. Mechanistically, OPCs orchestrate multi-pathway inhibition by destabilizing Wnt/β-catenin, Notch, PI3K/Akt/mTOR, JAK/STAT3, and Hedgehog pathways, triggering β-catenin degradation, silencing stemness regulators (OCT4, NANOG, SOX2), and stimulating tumor-suppressive microRNAs (miR-200, miR-34a). Furthermore, OPCs reorganize the tumor microenvironment by suppressing CSC markers (CD44, CD133, ALDH1, EpCAM) and reconstituting immune surveillance. Preclinical in-vitro and in-vivo models in colorectal, breast, and prostate cancers show OPC-mediated CSC elimination, apoptosis, and chemosensitization with minimal systemic toxicity. Emerging advances-redox-sensitive and pH-sensitive nanocarriers, exosome-based delivery, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 functional screens, and patient-derived organoids-present revolutionary solutions to overcome bioavailability bottlenecks and deliver precision-targeted therapies. These advances highlight the promise of OPCs as next-generation, multi-targeted anti-CSC oncology therapeutics.