Dissipative Particle Dynamics Study Of Interactions Between Virus-Like Nanoparticle And Cell Membrane

Due to the intrinsic physical and chemical properties of nanoparticles(NPs),they have been widely used in biomedical fields,such as drug delivery and cell imaging et al.However,some serious drawbacks still exist in the NP-based diagnostic and therapeutic applications,including the low internalization efficiency and side effects of NPs,which limit the further development of nanomedicine.In recent years,inspired by the unique spiky surface and superior transmission ability of virus,morphologically virus-like nanoparticles(VLPs)have been successfully synthesized,and it is experimentally demonstrated that the cellular uptake properties of NPs can be improved by mimicking the spiky surfaces of viruses.For instance,it is reported that the VLPs can achieve higher transmembrane efficiency and longer blood circulation time as compared with traditional NPs.However,this field is still in its infant stage and some intractable problems remain unresolved.Especially,the theoretical and simulation investigation on how the virus-like surface topology affects NP–membrane interactions has not been reported yet,and such investigation is envisioned to provide useful information for designing and optimizing NPs for versatile biomedical applications.Therefore,an in-depth understanding of the interactions between VLPs and membrane is essential for the development of VLPs for biomedical applications.In this work,dissipative particle dynamics(DPD)was employed to systematically investigate the internalization of VLPs,as well as the factors influencing VLP-membrane interactions.These studies provide an important theoretical guidance for the optimization and design of VLPs for biomedical applications.The main research contents in this thesis are summarized below.The microscopic mechanisms of the spikes of VLPs affecting the penetrability of VLPs have been clarified.By comparing the penetration process of VLPs and traditional NPs,it is verified the significant effect of the surface nanotopology on the penetrability of NPs.Moreover,by investigating the penetration process of different NPs,it is found that the presence of spikes can help to increase the lateral defects in the bilayer,decrease the vertical deformation of the bilayer,and lower the density of nearby lipids during the translocation process.These effects of spikes jointly contribute to the superior penetrability of VLPs.Furthermore,by comparing the transmembrane process and transmembrane efficiency of VLPs with different spike numbers and spike lengths,theoretical suggestions were put forward for improving the internalization efficiency of VLPs,which holds great promise for the development of NP-based diagnostic and therapeutic agents with advanced functionalities.The receptor-mediated endocytosis process of VLPs has been investigated,and the effects of the spike number and spike length on the endocytosis efficiency of VLPs have been analyzed.By comparing the dynamic process of receptor-mediated endocytosis of VLPs with different spike number and spike length,it is found that the spikes can produce biphasic effect on the receptor-mediated endocytosis efficiency of VLPs,meaning that the relative short spikes can enhance the endocytosis efficiency of VLPs,while relatively long spikes can hinder endocytosis process.Meanwhile,the effect of spike number on endocytosis efficiency of VLP is in significant.Further investigation on endocytosis process demonstrated that the effect of the spike length on the wrapping mode of the particle and the diffusion ability of the surrounding lipids is the main reason for the biphasic effect of spikes.The obtained results of this part serve as a foundation for future studies toward the rational design of VLPs with specific functions for biomedical applications.The influences of the hydrophobicity properties of the VLPs on the internalization efficiency and the cooperative behavior of VLPs have been clarified.The comparative study of the interactions between membrane and VLPs with different hydrophobicity arrangement demonstrates that the internalization efficiency of VLPs is mainly affected by the hydrophobicity of the spikes.The uptake efficiency of VLP can be improved with changing hydrophilic VLP spikes into hydrophobic spikes or amphiphilic block spikes.With the goal of controlling the dynamics behavior of VLPs in the practical applications,the multi-particle model was used to conduct further research on the cooperative behavior of VLPs during the internalization process.It is found that the cooperative effect is enhanced as the core of VLP changes from hydrophilic to hydrophobic.These findings highlight that the regulation of hydrophobicity arrangement of VLP can be an efficient strategy for controlling the VLPmembrane interactions.The effects of spike shape of VLPs on the non-specific and specific interaction between the VLPs and the cell membrane have been elucidated.Based on the VLPs in experimental studies,VLP models with different kinds of spike shape were built and investigated.By analyzing their penetration and receptor-mediated endocytosis process,the effects of spike shape on the internalization ability of VLPs were clarified.Moreover,with elucidating the underlying mechanisms of spike shape affecting the transmembrane efficiency of VLPs,the theoretical suggestions for optimization of VLPs were put forward,which serve as a foundation for future studies towards the development of VLP-based diagnostics and therapeutics.