Investigating the Role of Proteins and Lipids in the Prevention of Nanoparticle-Induced Cellular Membrane Damage Using Engineered Biomimetic Vesicles

Abstract

Background

Although nanoparticles are promising tools for novel therapeutics, there is a need to better understand different mechanisms of cellular nanotoxicity. Several studies have investigated the intracellular cytotoxicity of nanoparticles after entering cells via endocytosis, but the impact on the plasma membrane remains unclear. Giant plasma membrane vesicles (GPMVs) serve as powerful models to study nanoparticle–membrane interactions while preserving the native lipid and protein composition, and eliminating endocytosis interference. This study focuses on understanding the mechanism underlying the disruptive effects of nanoparticles on the cell membrane using biomimetic GPMVs.

Methods

A549 cells were chemically induced to generate GPMVs. GPMV-like, protein-free vesicles were also synthesized to understand the role of membrane proteins in nanotoxicity. Lipid exchange was then employed to investigate the function of lipids in membrane integrity. These vesicles were utilized to study the mechanisms of nanoparticle–membrane cytotoxicity. Additionally, this study introduced a novel repairing method that utilizes surface engineering and chemical alterations to reconstruct the pores formed during vesiculation, offering a new method to enhance the stability of biomembranes.

Results

This study is the first to demonstrate that membrane proteins significantly enhance the ability of biomembranes to interact and adsorb silica nanoparticles. Additionally, nanoparticle exposure induced more morphological damages in the protein-free compared to the protein-containing GPMVs. Furthermore, the exchange with glycerophospholipids containing one saturated acyl chain significantly improved the stability and fluidity of vesicles before and after exposure to different toxic nanoparticles. This work successfully introduces a new repairing technique for the loaded vesicles derived directly from the living cells to enhance the encapsulation efficiency and minimize the nanotoxicity.

Conclusion

In summary, membrane lipid saturation and selective protein incorporation are critical factors in nanoparticle binding, vesicle stability, and exogenously induced disruption of membrane-derived vesicles. These findings provide new insights into minimizing nanotoxicity while optimizing nanoparticle-based therapeutic applications.