Dynamic Cross-Linked Injectable Hydrogel for Synergistic Oxaliplatin– Resveratrol Therapy in Colorectal Cancer Peritoneal Metastasis

Peritoneal metastasis (PM) of colorectal cancer (CRC) remains a major therapeutic challenge due to the limited efficacy of current systemic and intraperitoneal treatments. To overcome these limitations, we developed an injectable, self-healing hydrogel constructed from a dual dynamic cross-linked network formed by borate ester and Schiff base bonds between phenylboronic acid-modified carboxymethyl chitosan (CMCS-PBA) and oxidized dextran (ODEX). This hydrogel was engineered for sustained intraperitoneal co-delivery of oxaliplatin (OXA) and resveratrol-loaded mesoporous silica nanoparticles (MSNs@RES). The system exhibited excellent biocompatibility and significantly inhibited cancer cell proliferation, migration, and invasion while inducing apoptosis and immunogenic cell death (ICD) in vitro. In a murine model of CRC peritoneal metastasis, the dual-drug-loaded hydrogel markedly suppressed tumor progression, reduced ascites formation, and prolonged survival. Proteomic analysis further revealed that treatment significantly modulated key signaling pathways, including HIF-1α-mediated angiogenesis, apoptosis-related cascades, and TGF-β-driven epithelial–mesenchymal transition (EMT). Collectively, this work presents a rationally designed localized delivery platform with significant potential for the treatment of colorectal cancer peritoneal metastasis.