In recent years, nanoparticles have evolved to a clinical modality to deliver diverse nucleic acids. Rising interest in nanomedicines comes from proven safety and efficacy profiles established by continuous efforts to optimize physicochemical properties and endosomal escape. However, despite their transformative impact on the pharmaceutical industry, the clinical use of non-viral nucleic acid delivery is limited to hepatic diseases and vaccines due to liver accumulation. Overcoming liver tropism of nanoparticles is vital to meet clinical needs in other organs. Understanding the anatomical structure and physiological features of various organs would help to identify potential strategies for fine-tuning nanoparticle characteristics. In this Review, we discuss the source of liver tropism of non-viral vectors, present a brief overview of biological structure, processes and barriers in select organs, highlight approaches available to reach non-liver targets, and discuss techniques to accelerate the discovery of non-hepatic therapies.
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