A conceptual scheme of the LipoGold tag design is illustrated in Figure . We explored several liposomal formulations to host the RR. Specifically, four liposomes' types were tested, composed of DOPC or POPC, which assemble into soft liquid-crystalline bilayers, and DSPC or DPPC, known to form rigid gel phase membranes in water. The lipid vesicles were prepared with a standardized methodology, involving the dissolution of the lipids in an organic solvent (CHCl3/MeOH mixture, refer to Materials and Methods for detailed procedures), which is then evaporated to yield a lipid film (see Materials and Methods); the film is then rehydrated followed by extrusion, to minimize lamellarity and polydispersity. RRs are small molecules, generally characterized by a pronounced hydrophobicity, deriving from the presence of aromatic groups, responsible for the Raman-active signals. A common RR employed to buildup SERS probes is 4-Mercaptobenzoic acid (4-MBA). To effectively integrate a hydrophobic RR within a liposomal membrane, a simple method involves co-dissolution, leading to a dry lipid film containing the RR. Upon hydration, the RR remains confined within the liposomal membrane. Employing this technique, DOPC, POPC, DPPC and DSPC liposomes embedding 4-MBA in the bilayer were prepared. To assess the capability of RR-laden liposomes to induce AuNPs' clustering, AuNPs dispersion were mixed with DOPC, POPC, DPPC, and DSPC liposomes containing 1% 4-MBA mol/mol. This interaction resulted in an abrupt shift in the characteristic color of AuNPs, from red to purple/blue, depending on the lipid composition. Figure presents UV-visible spectra of AuNPs collected after 30 minutes interaction with DOPC, POPC, DPPC, and DSPC liposomes. Clearly, the spectral features varied significantly, depending on the rigidity of the vesicles' bilayer. Specifically, the interaction of AuNPs with rigid vesicles (DPPC and DSPC) induced minimal plasmonic alterations, ascribable to changes in the AuNPs' dielectric environment following adhesion to the lipid membrane. Conversely, AuNPs incubated with soft vesicles (DOPC and POPC), exhibit more pronounced plasmonic variations. The dispersion color immediately turned blue and the spectra displayed the appearance of a shoulder (POPC, red curve) or even a welldefined red-shifted peak (DOPC, black curve). These spectral modifications are consistent with the formation of AuNPs' clusters, whose occurrence is templated by the lipid membrane. To visualize the AuNPs-liposome hybrids, Cryo-EM measurements were performed and representative Cryo-EM micrographs of AuNPs-DOPC and AuNPs-DPPC hybrids are presented in Figure and 1d, respectively. Across all cases, AuNPs adhere directly to the lipid bilayer without causing membrane disruption. In line with the plasmonic variations, AuNPs' interaction with soft DOPC(MBA) membranes leads to the formation of compact clusters where AuNPs are in direct contact. In contrast, interaction with rigid liposomes resulted in AuNPs adhering onto DPPC(MBA) membranes as individual entities, exhibiting larger interparticle spacing. Since these experimental results align with our recent studies on liposome-AuNPs interaction in the absence of RRs, it is reasonable to infer that the presence of MBA molecules embedded in the lipid bilayer does not substantially affect the overall interaction mechanism between citrate-capped AuNPs and zwitterionic vesicles. This occurrence can be attributed to the emergence of new hot-spots within the AuNPs clusters.