Lipid nanoparticles (LNPs) have emerged as a prominent drug delivery system for RNA therapeutics and have paved the way for next-generation vaccinations such as those against SARS-CoV-2. In addition to vaccines, LNPs can be targeted to offer organ and cell-type-specificity of protein expression or knockdown. Despite these promising applications, we have shown that different classes of LNPs have significant side effects due to several mechanisms. Firstly, we have shown that LNPs can induce severe inflammation and worsen markers of pre-existing inflammation by up to 10-fold. LNPs have been shown to activate the innate immune system across multiple administration routes and induce the secretion of pro-inflammatory cytokines and chemokines that promote the infiltration of activated leukocytes that damage tissues. This phenomenon limits the use of RNA-LNP therapeutics in any condition with inflammation such as ARDS, heart attack, and stroke (and in the background of comorbid infection and inflammation). Secondly, we have shown that in addition to inflammation, widely used LNPs with physicochemical tropism to the lung via cationic lipids induce coagulation. In this study, therefore, we identify and solve the side effects of LNPs to enable them to maximize their therapeutic potential. We show that LNPs' hallmark feature, endosomal escape, which is necessary for RNA expression, also directly triggers inflammation by causing endosomal membrane damage, and inhibition of severe endosomal damage sensing by galectins ameliorates this inflammation (Chapter 2). We also isolate the mechanisms through which cationic LNPs cause coagulation and investigate the optimal anticoagulation techniques that prevent side effects without affecting RNA expression (Chapter 3). Based on this, we demonstrate that a combination of affinity-moiety targeting and physicochemical tropism doubles LNP localization and RNA expression in the lungs, and markedly increases epithelial cell uptake (Chapter 4). Finally, we demonstrate therapeutic applications of targeted nanocarriers in the brain in models of inflammatory brain pathology (Chapter 5). In summary, our studies elucidate and ameliorate the side effects associated with LNPs and optimize their targeting to specific organs and cell types to generate safer LNPs that can be used for therapeutic , particularly for inflammatory diseases.