Highly Biocompatible Plasmonically Encoded Raman Scattering Nanoparticles Aid Ultrabright and Accurate Bioimaging.

Plasmonically engineered nanomaterials based on Au-Ag for surface-enhanced Raman scattering (SERS)-based biomedicine is of great importance but is still far behind clinical needs because of the poor compatibility between sensitivity and safety. Here, robust plasmonically encoded Raman scattering nanoparticles, named Au core-Raman-active molecule-Ag shell-Au shell nanoparticles (CMSS NPs), were synthesized. The as-developed CMSS NPs possess a unique exterior ultrathin Au shell (∼2.2 nm thickness) that plays double key roles as an effective wrapping layer as well as a plasmonic enhancing layer, thereby showing not only extraordinary stability against oxidative damages and bioerosion but also outstanding SERS sensitivity because of the stronger in-built electromagnetic field, achieving a significant SERS enhancement factor of 3.3 × 108. The results confirm that the individual CMSS NPs show ultrahigh brightness, reproducibility, selectivity, and biocompatibility in single-cell Raman imaging. Moreover, ultrabright in vivo tumor imaging with 1 × 1 mm2 area can be quickly achieved within 35 s under open-air condition. Furthermore, by secondary plasmonic encoding, the CMSS NPs flexibly serve as nanobeacon to monitor single-cell autophagy with improved accuracy. The CMSS NPs are expected as versatile SERS probes that enable ultrabright, fast, and precise Raman-based bioimaging and clinical bioapplications.