Lymph node targeting nanomedicines for tumor immunotherapy.

Abstract

Lymph nodes (LNs) are central hubs of adaptive immunity, orchestrating T cell activation and long-term immune surveillance, making them prime targets for cancer immunotherapy. However, their inherent immunosuppressive microenvironment and the systemic distribution of conventional therapies often limit antitumor efficacy and increase off-target toxicity. LN-targeted nanomedicines offer a promising strategy to overcome these limitations by enhancing antigen presentation, activating T cells within LNs, and reversing immunosuppression, while minimizing systemic exposure. Key strategies for LN targeting include: (1) passive targeting, where nanoparticle size, charge, and deformability are optimized to favor lymphatic uptake and LN accumulation; (2) active targeting, leveraging ligand-receptor interactions to selectively engage LN-resident immune cells or lymphatic structures; and (3) controlled drug release, enabling sustained and localized delivery to potentiate immunomodulatory effects. This review examines the immunosuppressive LN microenvironment and the barriers to effective nanomedicine delivery, then provides a comprehensive overview of LN-targeted nanomedicine designs, highlighting functional optimization strategies. By integrating mechanistic insights and design principles, we outline future directions for developing LN-targeted immunotherapies that enhance antitumor immunity, promote durable memory responses, and improve clinical translatability.