We have recently developed a bionanotechnology approach to vaccination (Reddy et al., Nature Biotechnology, 25, 1159-1164, 2007): degradable polymeric nanoparticles are designed that: (i) are so small that they can enter the lymphatic circulation by biophysical means; (ii) are efficiently taken up by a large fraction of dendritic cells (DCs) that are resident in the lymph node that drains the injection site; (iii) activate the complement cascade and provide a potent, yet safe, activation signal to those DCs; and (iv) thereby induce a potent, Th1 adaptive immune response to antigen bound to the nanoparticles, with the generation of both antibodies and cytotoxic T lymphocytes. In the present project, we focus on next-generation bionanotechnology vaccine platforms for vaccination. We propose three technological advances, and we propose to demonstrate those three advances in definitive models in the mouse. Specifically, we propose to (Specific Aim 1) evaluate the current approach of complement-mediated DC activation in breaking tolerance to a chronic viral infection (hepatitis B virus, HBV, targeting hepatitis B virus surface antigen, HBsAg) and to combine complement as a danger signal with other nanoparticle-borne danger signals to develop an effective bionanotechnological platform for therapeutic antiviral vaccination; (Specific Aim 2) to develop a new, ultrasmall nanoparticle implementation suitable for delivery of DNA to lymph node-resident DCs, also activating them, to enable more efficient DNA vaccination; and (Specific Aim 3) to develop an ultrasmall nanoparticle implementation suitable for delivery of DNA to DCs resident within the sublingual mucosa, also activating them, to enable efficient DNA mucosal vaccination. The Specific Aim addressing the oral mucosa will begin with HBsAg, to allow comparison to other routes of administration, and will then proceed to antigens from influenza A.