Deep tissue imaging in the second near‐infrared (NIR‐II) window holds great promise for widespread fundamental research. However, inhomogeneous signal attenuation due to tissue absorption and scattering hampers its application for accurate in vivo biosensing. Here, lifetime‐based in situ hepatocellular carcinoma (HCC) detection in NIR‐II region is presented using a tumor‐microenvironment (peroxynitrite, ONOO−)‐responsive lanthanide–cyanine Förster resonance energy transfer (FRET) nanosensor. A specially designed ONOO−‐responsive NIR‐II dye, MY‐1057, is synthesized as the FRET acceptor. Robust lifetime sensing is demonstrated to be independent of tissue penetration depth. Tumor lesions are accurately distinguished from normal tissue due to the recovery lifetime. Magnetic resonance imaging and liver dissection results illustrate the reliability of lifetime‐based detection in single and multiple HCC models. Moreover, the ONOO− amount can be calculated according to the standard curve.

Fluorescence imaging in the second near-infrared window (NIR-II, 1000–1700 nm) using small-molecule dyes has high potential for clinical use. However, many NIR-II dyes suffer from the emission quenching effect and extremely low quantum yields (QYs) in the practical usage forms. The AIE strategy has been successfully utilized to develop NIR-II dyes with donor–acceptor (D–A) structures with acceptable QYs in the aggregate state, but there is still large room for QY improvement. Here, we rationally designed a NIR-II emissive dye named TPE-BBT and its derivative (TPEO-BBT) by changing the electron-donating triphenylamine unit to tetraphenylethylene (TPE). Their nanoparticles exhibited ultrahigh relative QYs of 31.5% and 23.9% in water, respectively. By using an integrating sphere, the absolute QY of TPE-BBT nanoparticles was measured to be 1.8% in water. Its crystals showed an absolute QY of 10.4%, which is the highest value among organic small molecules reported so far. The optimized D–A interaction and the higher rigidity of TPE-BBT in the aggregate state are believed to be the two key factors for its ultrahigh QY. Finally, we utilized TPE-BBT for NIR-II photoluminescence (PL) and chemiluminescence (CL) bioimaging through successive CL resonance energy transfer and Förster resonance energy transfer processes. The ultrahigh QY of TPE-BBT realized an excellent PL imaging quality in mouse blood vessels and an excellent CL imaging quality in the local arthrosis inflammation in mice with a high signal-to-background ratio of 130. Thus, the design strategy presented here brings new possibilities for the development of bright NIR-II dyes and NIR-II bioimaging technologies.

To improve the bioimaging signal-to-noise ratio (SNR), long-term imaging capability,a nd decrease the potential biotoxicity,aninvivo cross-linking strategy was developed by using sub-10 nm, glutathione-modified, lanthanide nanoprobes.A fter administration, the nanoprobes cross-link in response to reactive oxygen species (ROS) at the inflamed area and enable the quicki maging of ROSi nt he second nearinfrared (NIR-II) window.These nanoprobes could be rapidly excreted due to their ultra-small size. This strategy may also be applied to other ultra-small contrast agents for the precise bioimaging by in situ lesion cross-linking.

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