In vivo Targeting of DNA Vaccines to Dendritic Cells via the Mannose Receptor Induces Long‐Lasting Immunity against Melanoma

Herein, we report effective, C‐type lectin mannose receptor (MR)‐selective, in vivo dendritic cell (DC)‐targeting lipid nanoparticles (LNPs) of a novel lipid‐containing mannose‐mimicking di‐shikimoyl‐ and guanidine head group and two n‐hexadecyl hydrophobic tails (DSG). Subcutaneous administration of LNPs of the DSG/p‐CMV‐GFP complex showed a significant expression of green fluorescence protein in the CD11c+ DCs of the neighboring lymph nodes compared to the control LNPs of the BBG/p‐CMV‐GFP complex. Mannose receptor‐facilitated in vivo DC‐targeted vaccination (s.c.) with the electrostatic complex of LNPs of DSG/pCMV‐MART1 stimulated long‐lasting (270 days post B16F10 tumor challenge) antimelanoma immunity under prophylactic conditions. Remarkably, under therapeutic settings, vaccination (s.c.) with LNPs of the DSG/pCMV‐MART1 complex significantly delayed melanoma growth and improved the survival of mice with melanoma. These findings demonstrate that this nonviral delivery system offers a resilient and potential approach to deliver DNA vaccines encoding tumor antigens to DCs in vivo with high efficacy. DNA vaccination: We report the design, syntheses and bioactivity evaluation of cationic amphiphiles containing mannose‐mimicking di‐shikimoyl‐(DSG) and di‐quinoyl‐(DQG) head groups as well as their control non‐mannosyl (BBG) analogues. We show that direct immunization with the electrostatic complexes of lipid nanoparticles of DSG/p‐CMV‐MART1 induces a long‐lasting protective immune response against B16F10 tumor challenge with remarkable memory response.