Bioorthogonal chemical imaging of solid lipid nanoparticles with minimal labeling by stimulated Raman scattering microscopy

Abstract

AbstractSolid lipid nanoparticles (SLNs) are a state‐of‐the‐art lipid‐based pharmaceutical drug delivery system. Advantages of SLNs include high biocompatibility, low immunogenicity, superiority in drug encapsulation capacity, and improved colloidal stability. They became widely known in late 2020, as several COVID‐19 vaccines are built upon SLNs technology. Despite the increasing impact, the characterization methods of SLNs are currently very limited especially in biological environment, which hinders fundamental understanding of the delivery mechanism and contributes to relatively low success rate in clinical translations. Here, we present close‐to‐label‐free imaging of deuterated SLNs using the emerging stimulated Raman scattering (SRS) microscopy. The introduction of deuterium to lipid structure renders bioorthogonal chemical specificity. Notably, with this approach, we have achieved ultrahigh single‐particle sensitivity both in vitro and in vivo, even with particle counting ability. Our bioorthogonal chemical imaging modality by SRS microscopy can be generalized to visualize a wide spectrum of lipid‐based drug carriers with high spatiotemporal resolution, chemical specificity, and ultimate sensitivity. This work opens up ways to address critical questions in SLN drug delivery and could also facilitate innovations in lipid nanotechnology and clinical translations.Key points Direct imaging of lipid nanocarrier that is the basis of the COVID‐19 vaccines. Novel single‐particle imaging technique applied to nanomedicine. Frontier of nanomaterial, optical imaging, and molecular pharmacology.