A Drug-Free Polysaccharide Hydrogel Encapsulating Iron Oxide Nanoparticles against Postoperative Tumor Recurrence and Metastasis

Surgical resection remains a cornerstone therapy for solid tumors, but the postoperative immunosuppressive microenvironment frequently causes tumor recurrence and metastasis. To address this critical challenge, we engineered a drug-free platform based on a dendrobium/chitosan-cross-linked polysaccharide hydrogel for localized postoperative immunotherapy. This biocompatible hydrogel matrix serves as a versatile depot for the sustained and pH-responsive release of folic-acid-functionalized iron oxide nanoparticles (Fe-Fol-NPs). The natural polysaccharide-based network not only ensures excellent biocompatibility and biodegradability but also provides a protective environment for the nanoparticles, facilitating their controlled delivery at the surgical site. Folate modification on the nanoparticles significantly enhances their intracellular delivery via the folate receptor β-overexpressing tumor-associated macrophages (TAMs). Mechanistic studies revealed that the Fe-Fol-NPs promoted M1-type polarization of TAMs via TLR4/NF-κB pathway activation, stimulating robust secretion of pro-inflammatory cytokines. This immunomodulatory effect triggered dendritic cell maturation and promoted cytotoxic T lymphocyte (CTL) differentiation, ultimately establishing a durable antitumor immunity. When implanted in a postoperative melanoma model, the Fe-Fol-NPs-laden polysaccharide hydrogel (Fe-Fol-NPs@Gel) demonstrated significant efficacy in preventing tumor recurrence and metastasis with an excellent safety profile. Our work underscores the potential of this polysaccharide hydrogel-based system as a promising and translational platform for postoperative adjuvant immunotherapy.