(261b) Lymphatic Targeting with Nanoparticles for Immunomodulation

The lymphatic system is a central part of the immune system, yet its therapeutic targeting for immunomodulation remains poorly characterized. We and others have shown that size is among the most important design criteria for targeting lymphatic vessels, with < 50 nm most efficiently taken up into dermal lymphatic vessels after intradermal injection. With this in mind, we have developed biofunctional nanoparticles that (i) are small enough to readily enter lymphatic vessels (~25 nm), (ii) are sensitive to oxidative environments (to degrade upon endocytosis), (iii) have surface characteristics to activate the complement system, and (iv) can readily be conjugated to protein or peptide antigens and adjuvant molecules. With these characteristics, our nanoparticles can efficiently deliver antigens to antigen-presenting cells in the lymph node, including immature dendritic cells and B cells, and induce cross-presentation and cross-priming of T cells when antigen is coupled via a reducible bond. We have characterized their biodistribution after intradermal, intranasal, and intrapulmonary delivery. With complement activation and with nanoparticle-conjugated CpG as danger signals, we demonstrate that nanoparticle-conjugated antigen can induce potent Th1-biased immune responses, both with intradermal and especially mucosal delivery. Finally, using tuberculosis (Tb) antigen 85b, we show enhanced protection in challenge studies with our nanoparticle-based delivery.