Lipid nanoparticle (LNP) technology, as currently one of the most promising and emerging technologies, shows the ability to deliver nucleic acid therapeutics for non-viral gene therapy (NVGT). The recent approvals of Onpattro and COVID-19 vaccines have demonstrated the feasibility, manufacturability and clinical safety of lipid based nano carriers. Compared to intramuscular vaccine delivery, intravenous (i.v.) delivery of a LNP formulation for gene therapy shows unique challenges. A LNP formulation for gene therapy via i.v. may require different lipid and formulation design. LNP tropism can be modulated via changing LNP physical and chemical properties (passive delivery) and adding targeting ligands (active targeting). In this talk, we will discuss the considerations and challenges in LNP development and impact on tissue targeting for NVGT.