Precision Targeting of Myeloid Cells via Peptide Dendrimer-Lipid Nanocarriers: A Novel Platform for Potent Cancer Immunotherapies.

Selective targeting of myeloid cells (MCs) holds therapeutic potential as an immuno-oncology approach. However, MC targeting using existing gene delivery platforms faces many barriers to clinical use, such as production scalability and off-target delivery to the liver and non-MCs. Here, a novel peptide dendrimer-lipid (PDL) nanocarrier for systemic administration, which overcomes many of these barriers, is characterized. This MC targeting nanocarrier (MCTN) is self-assembling, de-targets the liver, and selectively targets the spleen and MCs within the tumor microenvironment (TME). MCTN is validated as a cancer vaccine platform utilizing full-length antigens, generating robust immune responses with broad HLA-haplotype coverage. Finally, using a payload encoding constitutively active interferon regulatory factor 5 (IRF5), MCTN is found to suppress solid tumor growth and modulate the TME by improving CD8+ T-cell infiltration while depleting immunosuppressive cells.