A dual-responsive Luteolin nanoparticles suppresses colorectal cancer growth by targeting tumor angiogenesis

Abstract Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, and its current therapy is limited by chemoresistance and toxicity, underscoring an urgent unmet need for more effective and safer therapeutic strategies. Luteolin, a natural flavonoid with potent antiangiogenic properties, offers therapeutic promise, but its clinical utility is hampered by poor aqueous solubility. Here, we developed a dual-responsive polymeric nanoparticle platform by covalently conjugating Luteolin into a biocompatible poly(ethylene glycol) (PEG)-based polyurethane backbone to form Luteolin@PEG-600 nanoparticles. The resulting spherical nanoparticles (∼161 nm) demonstrated excellent colloidal stability and successfully amorphized Luteolin, greatly improving its apparent aqueous solubility. Crucially, the system remained stable at physiological pH (7.4) while exhibiting accelerated drug release in response to tumor-associated stimuli: acidic pH and reactive oxygen species. In vitro , the Luteolin@PEG-600 nanoparticles suppressed endothelial cell migration and tube formation by inhibiting the VEGF/VEGFR2 signaling pathway. In a CRC xenograft mouse model, the Luteolin@PEG-600 nanoparticles significantly suppressed tumor growth with no apparent systemic toxicity. Histological analysis of tumors confirmed that the treatment induced apoptosis, inhibited proliferation, and markedly reduced microvessel density. Transcriptomic analysis further confirmed that the nanoparticles concurrently downregulated the proangiogenic hypoxia pathway and activated apoptosis. Taken together, our findings demonstrate that this dual-responsive nanoparticle system overcomes Luteolin’s limitations, providing a safe and effective antiangiogenic and antitumor strategy that directly targets the VEGF/VEGFR2–hypoxia axis in CRC. This work validates the Luteolin@PEG-600 nanoparticles as a highly promising nanomedicine candidate for CRC therapy with clear potential for further preclinical development.