Published clinical data on the safety of mRNA-LNP vaccines are scarce, in comparison with siRNA, and are limited to local administration (ID and IM).

Although LNPs are promising delivery systems, safety issues need to be addressed to enable proper clinical development of LNP-formulated mRNA vaccines. LNPs’ potential toxicity could be complex and might manifest in systemic effects due to innate immune activation (induction of pro-inflammatory cytokine production), and/or in local, cellular toxicity due to accumulation of lipids in tissues (Hassett et al. 2019; Semple et al. 2010; Sabnis et al. 2018). Toxicity could potentially be abrogated, or reduced, by the administration of prophylactic anti-inflammatory steroids or other molecules and/or using biodegradable lipids (Hassett et al. 2019; Abrams et al. 2010; Tabernero et al. 2013; Tao et al. 2011). LNPs can also activate the complement system and might potentially elicit a hypersensitivity reaction known as complement activation-related pseudoallergy (CARPA) (Dezsi et al. 2014; Mohamed et al. 2019; Szebeni 2005, 2014), which can be alleviated using different strategies such as steroid and anti-allergic premedication (i.e., dexamethasone, acetaminophen, and antihistaminic drugs) or the use of low infusion rates during intravenous administration (Mohamed et al. 2019; Szebeni et al. 2018). Alternatively, co-delivery of regulatory cytokines (i.e., IL-10) using LNPs might be a viable strategy to reduce potential LNP-associated adverse events.