Bioinspired pH-sensitive liposomes for quercetin delivery to synergize with 5- FU in gastric cancer therapy

Gastric cancer is a major cause of cancer-related mortality on a global scale. Although 5-fluorouracil (5-FU) is a cornerstone chemotherapeutic for digestive tract malignancies, its efficacy is limited by dose-dependent toxicity and acquired resistance. Quercetin (QUC), a natural flavonoid, can sensitize tumor cells to 5-FU by modulating cell cycle-regulatory proteins. However, its limited water solubility and low bioavailability present significant limitations on its potential therapeutic application. In this study, we developed bioinspired pH-sensitive liposomes (NK-Lip@Q) functionalized for active targeting and acid-triggered drug release to enhance QUC delivery and synergistic anticancer activity with 5-FU. NK-Lip@Q exhibited a mean particle size of 206.36 ± 1.81 nm, an encapsulation efficiency of 60.69 ± 1.32 %, and a pH-dependent release profile with 72.75 ± 0.69 % cumulative release at pH 5.4. Cellular studies demonstrated efficient uptake by N87 cells, marked apoptosis induction (apoptosis ratio: 69.60 ± 8.71 %), and enhanced cytotoxicity in combination with 5-FU (Chou-Talalay combination index, CI = 0.68). In vivo, NK-Lip@Q could precisely accumulate in the target area, when co-administered with 5-FU, achieved significant tumor inhibition (tumor inhibition rate: 92.26 %) without obvious systemic toxicity. QUC complemented the anticancer action of 5-FU by regulating cell cycle-related genes, promoting apoptosis, and suppressing proliferation. In conclusion, this study demonstrates that NK-Lip@Q as a promising nanocarrier system that enhances the therapeutic performance of 5-FU by improving its synergistic antitumor efficacy in gastric cancer.