Complexity, unpredictability and safety challenges of lipid nanoparticles

The lipid nanoparticle (LNP) platform for delivering modified messenger RNA (modRNA) represents a transformative yet inherently complex and unpredictable technology. This narrative review synthesizes multidisciplinary evidence to explore the physicochemical basis, biological interactions, pharmacodynamic uncertainties, and safety challenges associated with LNPs and LNP-modRNA interactions. We describe how LNP self-assembly gives rise to variable structures with inconsistent modRNA payloads, as well as dynamic protein corona formation and aggregation phenomena that complicate the reliable characterization of these systems. After injection, LNPs undergo rapid biotransformation, including PEG-lipid shedding, biodistribution, and cellular uptake, which current analytical techniques cannot fully capture. Importantly, endosomal escape, which leads to the disruption of the endosome and the release of the payload, occurs within a narrow time window, is often inefficient, and results in inconsistent delivery. In addition, lipid metabolites, cell membrane modulation, and adduct formation raise poorly characterized safety questions. This review summarizes published evidence to inform future safety evaluations. It does not provide medical or clinical recommendations.