PT - JOURNAL ARTICLE AU - Enrico Lavagna AU - Davide Bochicchio AU - Anna L. De Marco AU - Zekiye P. Güven AU - Francesco Stellacci AU - Giulia Rossi TI - Ion-bridges and lipids drive aggregation of same-charge nanoparticles on lipid membranes AID - 10.1101/2021.11.22.468803 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.11.22.468803 4099 - http://biorxiv.org/content/early/2021/11/22/2021.11.22.468803.short 4100 - http://biorxiv.org/content/early/2021/11/22/2021.11.22.468803.full AB - The control of the aggregation of biomedical nanoparticles (NP) in physiological conditions is crucial as clustering may change completely the way they interact with the biological environment. Here we show that Au nanoparticles, functionalized by an anionic, amphiphilic shell, spontaneously aggregate in fluid zwitterionic lipid bilayers. We use Molecular Dynamics and enhanced sampling techniques to disentangle the short-range and long-range driving forces of aggregation. At short inter-particle distances, ion-mediated, charge-charge interactions (ion bridging) stabilize the formation of large NP aggregates, as confirmed by cryo-electron microscopy. Lipid depletion and membrane curvature are the main membrane deformations driving long-range NP-NP attraction. Ion bridging, lipid depletion, and membrane curvature stem from the configurational flexibility of the nanoparticle shell. Our simulations show, more in general, that the aggregation of same-charge membrane inclusions can be expected as a result of intrinsically nanoscale effects taking place at the NP-NP and NP-bilayer soft interfaces.Competing Interest StatementThe authors have declared no competing interest.