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Here, we report an unprecedented strategy for preparing polylactide\u2010cyclosporine A (PLA\u2010CsA) NPs (termed CsA\u2010NPs) through CsA\u2010initiated ring\u2010opening polymerization of lactide (LA) followed by nanoprecipitation. The resulting CsA\u2010NPs have sub\u2010100 nm sizes and narrow particle size distributions, and release CsA in a sustained manner without a \u201cburst\u201d\u2010release effect. Both free CsA and CsA\u2010NPs displayed comparable suppression of T\u2010cell proliferation and production of inflammatory cytokines in various T\u2010cell assays in a dose\u2010dependent manner. The IC\n                    <jats:sub>50<\/jats:sub>\n                    values for CsA and CsA\u2010NPs were 27.5 and 72.0 ng\/ml, respectively. As lymph nodes are the main loci for T\u2010cell activation, we coupled dendritic cells (DCs) with CsA\u2010NPs and successfully delivered CsA selectively to the lymph nodes. Our studies indicated that CsA\u2010NPs could be internalized in the DCs with a sustained release of CsA to the culture medium, suppressing alloreactive T\u2010cell proliferation. Allogeneic DCs loaded with CsA\u2010NPs were able to migrate to the draining lymph nodes where the T\u2010cell priming was significantly reduced without any systemic release. This innovative nanoparticulate CsA delivery technology constitutes a strong basis for future targeted delivery of immunosuppressive drugs with improved efficiency and reduced toxicity.\u2014Azzi, J., Tang, L., Tong, R., El Haddad, N., Akiyoshi, T., Mfarrej, B., Moore, R., Yang, S., Jurewicz, M., Ichimura, T., Lindeman, N., Cheng, J., Abdi, R. Polylactide\u2010cyclosporin A nanoparticles for targeted immunosuppression. 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