PEGylated lipids in lipid nanoparticle delivery dynamics and therapeutic innovation

Lipid nanoparticles (LNPs) have become significant vehicles in the delivery of therapeutic substances, particularly for nucleic acid vaccines and gene therapies. A key component in the nanoparticle formulation is polyethylene glycol-modified (i.e., PEGylated) lipids (PEG lipids), which can significantly influence the stability, cell interactions, and overall effectiveness of LNP delivery vehicles. This review collates insights into the role of PEG lipids in LNPs by illustrating how the PEG chains arrange on the nanoparticle surface and the potential impacts on LNPs' physicochemical properties by varying surface PEG density or PEG chemistry. Subsequently, PEG conformations are discussed in terms of their modulation of protein corona formation, cellular uptake, and immunogenic responses, particularly the pathways of anti-PEG antibody production and complement activation. Building on these understandings, functionalized PEG lipids are reviewed for ligand conjugation and targeted LNP delivery function. Promising alternatives to replace the benchmark PEG lipids are also systematically reviewed to address PEGylation associated immunogenicity. By conducting a critical analysis of the recent literature and identifying potent candidates for PEGylation strategies or PEG-free platforms, this review aims to provide insights and support the advancement of LNP mediated delivery.