Abstract

Tumor heterogeneity, immunosuppression, and frequent adverse effects present major challenges in colorectal cancer therapy. Although the combination of oxaliplatin (OXA, chemotherapy) and fruquintinib (FRU, antiangiogenic) shows clinical promise, their divergent physicochemical properties and inadequate tumor selectivity lead to suboptimal efficacy and systemic toxicity. To overcome the challenge, we developed a tumor-targeted nanosystem based on chitosan and fucoidan for co-delivery of hydrophilic oxaliplatin and hydrophobic fruquintinib (CS-Arg/Fuc-Bio@OF). The nanoparticle leverages the inherent P-selectin affinity of fucoidan and active targeting given by biotin modification to achieve precise tumor accumulation and microenvironment-responsive drug release. In vitro studies demonstrated that CS-Arg/Fuc-Bio@OF effectively eliminated HCT116 and HT29 cancer cells by inducing robust immunogenic cell death (ICD) and exerted potent anti-angiogenic effects. The combination of OXA-induced ICD with FRU-mediated angiogenesis suppression and polysaccharide-promoted immunomodulation synergistically reprogrammed the immunosuppressive tumor microenvironment, facilitating an effective anti-tumor immune response. In vivo, the nanoparticles significantly inhibited tumor growth and demonstrated good biosafety, with a hemolysis rate < 5% and no appreciable organ toxicity observed. This work not only validates CS-Arg/Fuc-Bio@OF as an efficient and safe combination therapy carrier but also provides a novel strategy for developing drug delivery systems based on natural polysaccharides.