In situ engineering of a self-healing drug-scaffold hydrogel to block platelet-driven postoperative metastasis.

Abstract

Surgical resection inadvertently promotes metastasis via platelet activation and tumor cell-platelet aggregation. Conventional postoperative therapies fail to address this early pro-metastatic window and lack precise local modulation. Herein, we develop an injectable self-healing hydrogel (CS@Art-2CHO/Cil gel) co-delivering artesunate (Art) and integrin inhibitor Cilengitide (Cil) for local application. Interestingly, we employ a "drug-as-structural-unit" design, where chemically engineered Art derivatives act as both active agents and intrinsic crosslinkers. They form a dynamic chitosan (CS) based network via Schiff base bonds, eliminating exogenous crosslinkers. By tuning aldehyde groups on Art, we precisely tailor crosslinking density and mechanical strength to a "mild yet stable" modulus suitable for the postoperative site. In this system, Art directly kills residual tumor cells, while Cil blocks integrin αvβ3 to inhibit platelet-tumor cell interactions. This dual "local clearance-systemic blockade" strategy synergistically prevents metastasis. This work presents a novel hydrogel paradigm that integrates precise mechanical adaptation with therapeutic synergy, offering a promising strategy against surgery-driven metastatic relapse.