Clinical approval of Lipid Nano Particles (LNP) for RNA heralded the advent of nanotechnology- based pharmacotherapy. Yet, RNA delivery to extra-hepatic sites remains a major unmet challenge. Weissman pioneered modifications of mRNA providing effective translation in diverse cell types, while Muzykantov introduced “vascular targeting”, nanomedicine strategy for drug delivery to desired areas in the vasculature. Here we converge these advances to devise nanocarriers targeting RNA to desired sites of transgene synthesis and therapeutic action. We found that ligands of Inter-Cellular Adhesion Molecule-1 (ICAM) conjugated to nanocarriers, direct ICAM-LNP (ILNP) to accumulate in lungs, especially, in the inflamed lungs, with trivial cerebral uptake. In opposite, LNP targeting to Vascular Cell Adhesion Molecule-1 (VCAM) provides trivial pulmonary uptake of VCAM-LNP (VLNP), and selective uptake in the inflamed brain, surpassing the benchmarks by orders of magnitude. VLNP loaded with mRNA encoding endothelial multifunctional anti-thrombotic and anti-inflammatory protein thrombomodulin (TM) provides transgene synthesis and protective effect in the inflamed CNS unrivaled by other agents. We will characterize and if needed reiteratively re-engineer targeting features of this powerful nanotechnology platform, by pursuing the following Specific Aims. Aim 1: Multi-scale spatiotemporal mapping of vascular targeting of ILNP and VLNP. Using isotope tracing and real time imaging, in vivo microscopy and flow cytometry, we will define PK/BD, dynamics of LNP localization and reporter transgene activity in the sites of desirable therapeutic action. Aim 2: Targeting therapeutic thrombomodulin RNA to lung and brain. We will characterize salient parameters of TM transgene expression, beneficial and unintended effects of ILNP and VLNP in naive mice and in mouse models of pulmonary and cerebral inflammation. Aim 3: Translational development of LNP. We will upgrade LNP to clinically applicable format via site-specific conjugation of small recombinant ligands. This study will define key specification parameters of a novel nanotechnology platform for selective delivery of RNA to desirable cells and cellular compartments in brain, lungs and likely other organs. It will establish proof of principle for a new nanomedicine approach for effective, specific and safe biological pharmacotherapy of ALI and stroke, with future expansion to other diseases.