Engineered In-Situ-Forming Biomimetic Hydrogel with Self-Regulated Immunostimulatory Capacity Promotes Postoperative Tumor Treatment

Abstract

Post-resection tumors with microscopic foci and immunosuppressive microenvironments have high risk of recurrence and metastasis but respond poorly to various therapies. Herein, we propose a biomimetic hydrogel as a biocompatible, biodegradable and bioadhesive postoperative dressing that could be formed in situ by NaIO4-initiated thiourea-catechol crosslinking after syringe-injection into the resection cavity. The thiourea or catechol-bearing hyaluronic acid (HA) precursors are also separately engineered with phenylboronic acid and β-cyclodextrin (β-CD) groups, potentiating the reversible immobilization of (1S, 3R) RAS-selective lethal 3 (RSL3) and glycosylated granulocyte macrophage-colony stimulating factor (GM-CSF) without invasive chemical reactions. Meanwhile, the interconnected porous superstructure of the hydrogels allows the incorporation and self-regulated delivery of PD-L1 antibody (aPD-L1). RSL3-induced immunogenic ferroptosis and GM-CSF could cooperatively trigger robust adaptive tumor-specific immune responses, while aPD-L1 further alleviates the accumulated immunoresistance of tumor cells due to interferon γ-mediated PD-L1 upregulation, thus stimulating potent local and whole-body antitumor immunity to prevent postoperative tumor recurrence and metastasis. The biomimetic hydrogel may serve as a promising solution for the postoperative treatment of solid tumors.