Nanoparticle (NP) aggregation can not only change the unique properties of NPs but also affect NP transport and membrane penetration behavior in biological systems. Coarse-grained (CG) molecular dynamics (MD) simulations were performed in this work to investigate the aggregation behavior of NPs with different properties in ionic solutions under different temperature conditions. Four types of NPs and NP aggregates were modeled to analyze the effects of NP aggregation on NP translocation across the cell membrane at different temperatures. Hydrophilic modification and surface charge modification inhibited NP aggregation, whereas stronger hydrophobicity and higher temperature resulted in a higher degree of NP aggregation and a denser structure of NP aggregates. The final aggregation percentage of hydrophobic NPs in the NaCl solution at 37 °C is 87.5%, while that of hydrophilic NPs is 0%, and the time required for hydrophobic NPs to reach 85% aggregation percentage at 42 °C is 6 ns, while it is 9.2 ns at 25 °C. The counterions in the solution weakened the effect of surface charge modification, thereby realizing good dispersity. High temperature could promote the NP membrane penetration for the same NP, while it also could enhance the NP aggregation which would increase the difficulty in NP translocation across cell membrane, especially for the hydrophobic NPs. Therefore, suitable surface modification of NPs and temperature control should be comprehensively considered in promoting NP membrane penetration in biomedical applications.

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