This study explores the use 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. After intradermal injection, ultra-small nanoparticles (25 nm) efficiently entered lymphatic capillaries and draining lymph nodes, targeting half of the lymph node-residing dendritic cells, while 100-nm nanoparticles were only 10% as efficient. The surface chemistry of these nanoparticles activated the complement cascade, generating a danger signal in situ and potently activating dendritic cells. Using nanoparticles conjugated to the model antigen ovalbumin, the study demonstrated the generation of humoral and cellular immunity in mice in a size- and complement-dependent manner. The study highlights two alternative strategies for vaccination: interstitial-to-lymphatic flow to deliver antigen and adjuvant to lymph node-resident dendritic cells, and in situ complement activation to mature these cells. The nanoparticles used in this study were Pluronic-stabilized polypropylene sulfide (PPS) nanoparticles, which have a hydrophobic core of crosslinked PPS and a hydrophilic surface corona of Pluronic. These nanoparticles were designed to target lymph node-resident dendritic cells and activate complement through their polyhydroxylated surfaces. The study found that 25-nm polyhydroxylated nanoparticles induced dendritic cell maturation, as evidenced by upregulation of the maturation markers CD86, CD80, and CD40. These nanoparticles also induced antigen-specific adaptive immune responses, including humoral and cellular immunity. The study demonstrated that the complement activation was essential for inducing dendritic cell maturation and subsequent immune responses. The results suggest that nanoparticles engineered to both target lymph nodes and strongly activate complement are potent maturation stimuli for dendritic cells. The study also found that the complement activation was necessary for inducing humoral immunity, as C3-deficient mice showed significantly lower antibody titers when injected with 25-nm polyhydroxylated-ovalbumin nanoparticles compared to wild-type controls. The study concludes that the use of nanoparticles as a vaccine platform, targeting lymph node-resident dendritic cells and activating complement, is a promising approach for inducing adaptive immunity. The study also highlights the importance of further research into the toxicity, elimination, and molecular interactions between complement and dendritic cells to demonstrate the reported system as more than an implementation to explore these strategies.This study explores the use 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. After intradermal injection, ultra-small nanoparticles (25 nm) efficiently entered lymphatic capillaries and draining lymph nodes, targeting half of the lymph node-residing dendritic cells, while 100-nm nanoparticles were only 10% as efficient. The surface chemistry of these nanoparticles activated the complement cascade, generating a danger signal in situ and potently activating dendritic cells. Using nanoparticles conjugated to the model antigen ovalbumin, the study demonstrated the generation of humoral and cellular immunity in mice in a size- and complement-dependent manner. The study highlights two alternative strategies for vaccination: interstitial-to-lymphatic flow to deliver antigen and adjuvant to lymph node-resident dendritic cells, and in situ complement activation to mature these cells. The nanoparticles used in this study were Pluronic-stabilized polypropylene sulfide (PPS) nanoparticles, which have a hydrophobic core of crosslinked PPS and a hydrophilic surface corona of Pluronic. These nanoparticles were designed to target lymph node-resident dendritic cells and activate complement through their polyhydroxylated surfaces. The study found that 25-nm polyhydroxylated nanoparticles induced dendritic cell maturation, as evidenced by upregulation of the maturation markers CD86, CD80, and CD40. These nanoparticles also induced antigen-specific adaptive immune responses, including humoral and cellular immunity. The study demonstrated that the complement activation was essential for inducing dendritic cell maturation and subsequent immune responses. The results suggest that nanoparticles engineered to both target lymph nodes and strongly activate complement are potent maturation stimuli for dendritic cells. The study also found that the complement activation was necessary for inducing humoral immunity, as C3-deficient mice showed significantly lower antibody titers when injected with 25-nm polyhydroxylated-ovalbumin nanoparticles compared to wild-type controls. The study concludes that the use of nanoparticles as a vaccine platform, targeting lymph node-resident dendritic cells and activating complement, is a promising approach for inducing adaptive immunity. The study also highlights the importance of further research into the toxicity, elimination, and molecular interactions between complement and dendritic cells to demonstrate the reported system as more than an implementation to explore these strategies.