Liposomal coating of near infrared resonant magnetic-plasmonic nanostars for blood-brain barrier-like passage, selective targeting, and bioorthogonal surface-enhanced Raman scattering imaging.
Abstract
HYPOTHESIS A flexible phospholipid bilayer can conformally coat highly anisotropic iron oxide@gold nanostars (M@NSts), maintain colloidal stability over 7 days, and preserve magnetic manipulability and near-infrared (NIR) plasmonic properties. Embedding a hydrophobic bioorthogonal Raman reporter within the membrane should enable background-free surface-enhanced Raman scattering (SERS) without prior immobilization on gold, while the biomimetic interface should promote endothelial transport and molecular targeting. The resulting modular architecture may also support future therapeutic cargo loading. EXPERIMENTS Reduced-size iron oxide nanoflowers retaining their multicore magnetic architecture were decorated with gold seeds and grown into M@NSts. Reporter-loaded liposomes composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and poly(ethylene glycol) (PEG)-conjugated 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine bearing terminal carboxyl groups (DOPE-PEG-COOH) were osmotically ruptured and reassembled around the nanostars to form flexible, bioconjugatable coatings. Transwell assays compared lipid-coated and PEGylated M@NSts across endothelial colony-forming cell (ECFC) and blood-brain barrier (BBB)-relevant human brain microvascular endothelial cell (HBEC-5i) monolayers. Transport into the basolateral compartment was quantified by nanoparticle tracking analysis (NTA) and inductively coupled plasma atomic emission spectroscopy (ICP-AES), followed by magnetic enrichment and SERS analysis. Cholera toxin subunit B (CT-B)-mediated recognition of monosialotetrahexosylganglioside (GM1) was assessed. FINDINGS The optimized synthesis reduced nanoflower diameter from 130 ± 20 to 70 ± 10 nm while preserving magnetic responsiveness. The bilayer conformed to the spiky surface and preserved NIR plasmonic activity while positioning the reporter near gold for efficient SERS enhancement. The probes displayed a background-free band at 2218 cm-1 and remained colloidally and spectroscopically stable for seven days. Lipid-coated M@NSts showed 1.8- and 3.1-fold higher transport than PEGylated controls across ECFC and the more restrictive HBEC-5i monolayers, respectively. Basolateral SERS detection after magnetic enrichment supported preservation of the lipid-nanostar association. Enhanced transport occurred with moderate permeability changes but no significant monolayer disruption. As proof of concept, conjugation with CT-B promoted specific recognition of cellular GM1. The lipid interface therefore integrates stabilization, magnetic recovery, bioorthogonal detection, endothelial transport, and molecular targeting.