Protocatechuic Acid-Based Supramolecular Hydrogel Targets SerpinB9 to Achieve Local Chemotherapy for OSCC.

Protocatechuic acid (PCA) is a natural phenolic acid present in daily vegetables and fruits. Notably, PCA was demonstrated to inhibit the biological function of SerpinB9 (Sb9) and exhibit an excellent antitumor effect, showing great potential in cancer treatment. However, the short half-life time limits PCA's wide application against cancers. To overcome this shortage of PCA, we integrated PCA and another natural product with strong self-assembling properties, isoguanosine (isoG), to develop a novel multifunctional supramolecular hydrogel with good biocompatibility and injectability, which remarkably lengthens the releasing time of PCA and exerts considerable anticancer effects in vitro and in vivo. Besides, we surprisingly found that PCA could not only target Sb9 but also restrain cancer development through activating the JNK/P38 pathway, decreasing the ROS level, and repairing cancer stemness. In all, our results demonstrate that this PCA-based hydrogel could act as a multifunctional hydrogel system equipped with considerable anticancer effects, providing potential local administration integrating with targeted therapy and chemotherapy in one simple modality.