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To accomplish this, gene delivery systems must overcome multiple intra\u2010 and extracellular barriers to avoid rapid clearance from the body and\/or significant accumulation in off\u2010target sites which can lead to undesired side effects (e.g., genotoxicity, immunogenicity). This requires an in\u2010depth knowledge of biomolecular and biophysical interactions at the nano\u2013bio interface to engineer gene vectors which preferentially access specific organs such as the liver, spleen, and brain after systemic administration. In this review, we will discuss the strategies employed to engineer genetic therapies which selectively target organs of interest after systemic administration. We focus on three major classes of nucleic acid delivery systems including adeno\u2010associated viruses, lipid nanoparticles, and polymeric nanoparticles (PNPs) which are all being explored for tissue\u2010specific gene delivery. 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