Nanoengineered Biomaterials Manipulating Lymph Nodes for Effective Cancer Immunotherapy

Lymph nodes are central sites for the priming of antitumor adaptive immunity. However, free antigens, adjuvants, cytokines, and nucleic acid-based immunomodulators rarely accumulate within them at concentrations that are sufficient for engaging dendritic and T cell-rich regions with precision. Tumor-draining lymph nodes are also frequently remodelHed into immunosuppressive niches, which further limits immunotherapy efficacy. Biomaterials can be programmed to intervene in lymph-node delivery and immune regulation through the rational design of their particle size, surface charge, surface chemistry, ligand modification, and stimuli-responsive release. This review summarizes recent progress in biomaterial-mediated lymph-node engineering for cancer immunotherapy. We highlight two delivery routes, namely passive drainage and active targeting, and discuss how biomaterials achieve the spatiotemporal coordination of dendritic-cell activation, major histocompatibility complex class I cross-presentation, and T cell priming within lymph nodes. We further examine strategies for constructing artificial lymphoid tissues, including 3D-printed scaffolds and the induction of tertiary lymphoid structures, and discuss the opportunities and challenges of clinical translation. These advances offer new engineering perspectives for developing lymph node-targeted delivery systems toward clinical use.