Synergistic effects arising from the conjugation of organic dyes onto non-luminescent metal nanoparticles (NPs) have greatly broadened their applications in both imaging and sensing. Herein, we report that conjugation of a well-known pH-insensitive dye, tetramethyl-rhodamine (TAMRA), to pH-insensitive luminescent gold nanoparticles (AuNPs) can lead to an ultrasmall nanoindicator that can fluorescently report local pH in a ratiometric way. Such synergy originated from the dimerization of TAMRA on AuNPs, of which geometry was very sensitive to surface charges of the AuNPs and can be reversely modulated through protonation of surrounding glutathione ligands. Not limited to pH-insensitive dyes, this pH-dependent dimerization can also enhance the pH sensitivity of fluorescein, a well-known pH-sensitive dye, within a larger pH range, opening up a new pathway to design ultrasmall fluorescent ratiometric nanoindicators with tunable wavelengths and pH response ranges.
KeywordsGold Nanoparticle; Luminescence; Dimerization; Dye; pH Metal nanoparticles (NPs) generally do not fluoresce because of their large density of states; as a result, conjugation of organic dyes to non-luminescent metal NPs is essential for visualizing them in fluorescence imaging systems. [1] . For instance, Chan et al. conjugated organic dyes such as Cyto633 to different sized non-luminescent gold NPs (AuNPs), so that these AuNPs can be readily monitored in real time in vivo [2] . Moreover, this simple approach also creates many synergistic effects that can further broaden imaging and sensing applications of both organic dyes and metal NPs. For example, by loading organic dyes onto plasmonic metal NPs, giant Raman scattering with specific molecular signatures of organic dyes has been used for multispectral cancer imaging [3] . By taking advantage of the fluorescence quenching effect of AuNPs, dye-AuNP complexes can be used as sensors for detecting ssDNA, proteins, small toxins, etc [4] .Correspondence to: Jie Zheng. ‡ These authors contributed equally to this work
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Author ManuscriptDifferent from conventional non-luminescent metal NPs, a new class of metal NPs that can give intrinsic fluorescence without being labeled with organic dyes has also emerged in the past decade [5] . By tuning particle size, crystallinity, surface ligands and valance states, we and others were able to create a large number of luminescent metal NPs with tunable emission ranging from UV to NIR [6] . Complementary to dye-labeled non-luminescent metal NPs, metal NPs with intrinsic emissions have also found many applications in imaging and sensing. For instance, red-emitting AuNPs have been used to detect small metal ions, toxin and reactive oxygen species [7] . More recent studies show that NIR-emitting AuNPs can serve as a new class of renal clearable contrast agents for rapid tumor diagnosis and kidney functional imaging [8] . While the emergence of these luminescent metal NPs suggests that or...
