Multi-epitope ligand-conjugated nanoparticles for tumor neoantigen targeting: advancing molecular precision in cancer immunotherapy.

Tumor neoantigens, derived from somatic mutations unique to cancer cells, represent a novel class of highly specific targets for precision immunotherapy. Their absence in normal tissues minimizes the risk of central tolerance, offering the potential to elicit tumor-specific immune responses. MEL-NPs are engineered to display multiple neoepitope peptides on their surface as antigenic cargo while incorporating targeting ligands-such as antibodies or aptamers-that promote specific uptake by dendritic cells. This dual-functionalization enables both antigen presentation and active delivery to immune-priming sites. However, their clinical application is often hindered by low abundance, inefficient antigen presentation, and limited delivery to antigen-presenting cells (APC) Nanoparticle-based delivery platforms have emerged as transformative tools to address these challenges by enhancing neoantigen stability, promoting tumor-site accumulation, and improving immune co-stimulation. Among them, multi-epitope ligand-conjugated nanoparticles (MEL-NPs) represent a next-generation strategy that enables modular co-display of multiple neoepitopes and targeted delivery to tumor-infiltrating dendritic cells (DCs). This multivalent configuration enhances antigen uptake, cross-presentation, and activation of polyclonal CD8⁺ and CD4⁺ T cell responses. The review discusses the molecular landscape of neoantigens, advances in nanoparticle engineering, immune activation pathways, and preclinical/clinical data supporting MEL-NPs. By integrating molecular specificity with immunological breadth, MEL-NPs offer a promising platform to overcome tumor heterogeneity and immune evasion in personalized cancer immunotherapy.