This study investigates the potential of nanoparticles as a vaccine platform by targeting lymph node-residing dendritic cells via interstitial flow and activating these cells through in situ complement activation. Ultra-small nanoparticles (25 nm) were found to efficiently target lymph node-residing dendritic cells after intradermal injection, while larger nanoparticles (100 nm) were less effective. The surface chemistry of these nanoparticles activated the complement cascade, generating a danger signal that potently activated dendritic cells. Using nanoparticles conjugated with the model antigen ovalbumin, the researchers demonstrated the generation of both humoral and cellular immunity in mice, which was size- and complement-dependent. The study highlights the potential of lymphatic transport and complement activation as novel strategies for vaccine development, offering a promising approach to target lymph node-resident dendritic cells and induce adaptive immune responses.This study investigates the potential of nanoparticles as a vaccine platform by targeting lymph node-residing dendritic cells via interstitial flow and activating these cells through in situ complement activation. Ultra-small nanoparticles (25 nm) were found to efficiently target lymph node-residing dendritic cells after intradermal injection, while larger nanoparticles (100 nm) were less effective. The surface chemistry of these nanoparticles activated the complement cascade, generating a danger signal that potently activated dendritic cells. Using nanoparticles conjugated with the model antigen ovalbumin, the researchers demonstrated the generation of both humoral and cellular immunity in mice, which was size- and complement-dependent. The study highlights the potential of lymphatic transport and complement activation as novel strategies for vaccine development, offering a promising approach to target lymph node-resident dendritic cells and induce adaptive immune responses.