Functionalized Carbon Dots With Intrinsic Wnt/β-Catenin Inhibition to Synergistically Promote 5-Fluorouracil Chemotherapy

5-fluorouracil (5-FU) is the most widely used anti-pyrimidine drug that exerts its cytotoxic effect by causing DNA damage. The Wnt/β-catenin pathway has been considered a promising strategy to improve chemosensitivity by enhancing the DNA damage response of chemotherapy drugs. Combination therapies against cancers could inevitably affect endogenous levels of ribonucleotides (RNs) and deoxyribonucleotides (dRNs) which are critical for DNA synthesis and repair. However, exploring satisfactory Wnt/β-catenin inhibitors for synergistic therapy through regulating RNs and dRNs remains challenging. Here, aloe vera-derived carbon dots (A-CDs) with good bioactivity were synthesized via a one-step hydrothermal process, demonstrating both intrinsic Wnt/β-catenin inhibition and bioimaging capabilities to overcome the limitations of conventional Wnt/β-catenin inhibitors. The as-prepared A-CDs were further served as the transport vehicle for 5-FU, facilitating synergistic combination therapy by inhibiting the Wnt/β-catenin pathway, which could possibly accelerate nucleotide imbalance of dATP, ATP, TMP, and dUMP, ultimately leading to enhanced 5-FU efficiency. Additionally, the tumor-targeted material (HA-CDs@5-FU) was synthesized by modifying hyaluronic acid (HA) onto CDs@5-FU and exhibited superior antitumor efficacy in vivo with negligible side effects. Overall, this study provided a novel strategy for Wnt/β-catenin inhibition and synergistic therapy, providing insights into the application of nano-agents in cancer therapy.