Multifunctional compact hybrid Au nanoshells: a new generation of nanoplasmonic probes for biosensing, imaging, and controlled release.

Gold nanoshells (AuNSs) with tunable localized surface plasmon resonance (LSPR) peaks in the near-infrared (NIR) region possess unique optical properties-particularly that soft tissues are "transparent" at these wavelengths-making them of great interest in cancer diagnosis and treatment. Since 1998 when Halas and co-workers invented the first generation of AuNS, with a silica core and Au shell, researchers have studied and designed AuNSs for theranostic-individualized, combination diagnosis and therapy-nanomedicine. As demand has increased for more powerful and practical theranostic applications, so has demand for the next generation of AuNSs-compact yet complex multifunctional AuNSs with finely integrated plasmonic and nonplasmonic inorganic components. For in vivo biomedical applications, such a hybrid AuNS offers the desirable optical properties of NIR LSPR. Size, however, has proved a more challenging parameter to control in hybrid AuNSs. The ideal size of therapeutic NPs is 10-100 nm. Larger particles have limited diffusion in the extracellular space, while particles less than 5 nm are rapidly cleared from the circulation through extravasation or renal clearance. Conventional methods of preparing AuNS have failed to obtain small-sized hybrid AuNSs with NIR LSPR responses. In this Account, we present a new class of multifunctional hybrid AuNSs with ultrathin AuNSs and varied, functional (nonplasmonic) core components ranging from "hard" semiconductor quantum dots (QDs), to superparamagnetic NPs, to "soft" liposomes made using poly-l-histidine as a template to direct Au deposition. The resultant hybrid AuNSs are uniform and compact (typically 15-60 nm) but also preserve the optical properties and shell-type NIR response necessary for biomedical use. We also demonstrate these particles' innovative plasmonic applications in biosensing, multimodal imaging and controlled release. More importantly, the magnetic-plasmonic Fe3O4/Au core-shell NP enables a new biological imaging method-magnetomotive photoacoustic (mmPA) imaging, which suppresses the nonmagnetomotive background and therefore offers remarkable contrast enhancement and improved specificity compared with photoacoustic images using conventional NP contrast agents. The advantages of our AuNSs are obvious: they are monodisperse, small (<100 nm), highly integrated, and have tunable visible-NIR plasmonic responses. All of these properties are crucial for in vitro or in vivo biological/biomedical studies and many applications, especially for studies of single cells or molecules which require particle monodispersity and tight size control. The plasmonic fluorescent QD/Au and the magnetic plasmonic Fe3O4/Au core-shell NPs may also reveal new physical phenomena that may lead to useful applications, owing to their well-defined core-shell nanoarchitectures and underlying nanoscale physical interactions.