All-Small-Molecule Supramolecular Hydrogel Combining Self-Delivery and ROS-Responsive Release for Inhibiting Tumor Growth and Postoperative Recurrence

Supramolecular hydrogels show unprecedented advantages and have attracted widespread attention in biomedical sciences. However, it is challenging for bioactive star molecules, such as celastrol, to meet ideal formation conditions. Here, we report a dynamic covalent method to construct a dihydrol-type celastrol-phenylenediboronic acid-guanosine (DHcelPBG) supramolecular hydrogel. The DHcelPBG hydrogel can effectively accelerate 4T1 cell apoptosis by modulating the PI3K/Akt signaling pathway. Especially, the DHcelPBG hydrogel can serve as a self-delivery platform for reactive oxygen species (ROS)-facilitated self-release. An excessive ROS-containing tumor microenvironment can promote the obtained DHcelPBG hydrogel to kill more 4T1 tumor cells. Meanwhile, the hydrogel also exhibits distinguished degradability and biocompatibility. Subsequently, the orthotopic 4T1 tumor model results further demonstrate that the DHcelPBG hydrogel remarkably inhibits tumor growth and does not damage healthy tissue. In the postoperative recurrence 4T1 tumor model, the DHcelPBG hydrogel also effectively prevents postoperative tumor recurrence and lung metastasis without causing adverse side effects, resulting in an extended lifetime. The DHcelPBG hydrogel also exhibits distinguished degradability and biocompatibility. The DHcelPBG hydrogel integrates ROS-responsiveness, localized self-delivery, and antitumor activity into one system for breast cancer treatment with fewer side effects, showing great potential for clinical transformation in cancer therapy.