Cross-presentation is important for cellular immunity against pathogens and cancer.

Biomimetic vaccines can be designed to enhance antigen presentation on MHC-I.

Nanoparticles increase lymphatic antigen transport and uptake by dendritic cells.

Endosomal escape opens access to cytosolic MHC-I antigen-processing pathway.

Coordinated co-delivery with adjuvants enhances cross-priming of T cells.

Cross-presentation of exogenous antigen on MHC class-I is a crucial process for generating a CD8+ T cell response, and is therefore an important design consideration in the development of T-cell-engaging vaccines against viruses, intracellular bacteria, and cancers. Here, we briefly summarize known cross-presentation pathways and highlight how synthetic vaccines can be engineered to enhance MHC-I presentation of exogenous peptide and protein antigens by professional antigen-presenting cells (APCs). In particular, we summarize how molecular engineering and nanotechnology are being harnessed to enhance antigen delivery to lymph nodes and to cross-presenting dendritic cells, to bypass endosomal trafficking of exogenous antigen to promote delivery of antigen to the cytosol of APCs, and to coordinate the delivery of antigen with immune-stimulating adjuvants that can act synergistically to augment antigen cross-presentation.

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