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Gold nanoparticles (AuNPs) encapsulated within reconstituted phospholipid bilayers have been utilized in various bioapplications due to their improved cellular uptake without compromising their advantages. Studies have proved that clustering AuNPs can enhance the efficacy of theranostic effects, but controllable aggregation or oligomerization of AuNPs within lipid membranes is still challenging. Here, we successfully demonstrate the formation of gold nanoparticle clusters (AuCLs), supported by reconstituted phospholipid bilayers with appropriate sizes for facilitating cellular uptake. Modulation of the lipid membrane curvatures influences not only the stability of the oligomeric state of the AuCLs, but also the rate of cellular uptake. Dynamic light scattering (DLS) data showed that 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), with its relatively small head group, is crucial for establishing an effective membrane curvature to encapsulate the AuCLs. The construction of phospholipid bilayers surrounding AuCLs was confirmed by analyzing the secondary structure of M2 proteins incorporated in the lipid membrane surrounding the AuCLs. When AuCLs were incubated with cells, accumulated clusters were found inside the cells without the lipids being removed or exchanged with the cellular membrane. We expect that our approach of clustering gold nanoparticles within lipid membranes can be further developed to design a versatile nanoplatform

Lipid Reconstitution-Enabled Formation of Gold Nanoparticle Clusters for Mimetic Cellular Membrane