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Metformin (MET) is currently the first-line treatment for type 2 diabetes mellitus (T2DM). However, overdose and long-term use of MET may induce a serious liver injury. What’s worse, diagnosis of MET-induced liver injury remains challenging in clinic. Although several probes have been reported for imaging MET-induced liver injury utilizing upregulated hepatic H2S as a biomarker, they are still at risk of nonspecific activation in complex physiological environments and rely on light excitation with limited imaging depth. Herein, we rationally designed and developed a dual-locked probe, DPA-H2S, for precise imaging of MET-induced liver injury by H2S-activated sonoafterglow luminescence. DPA-H2S is a small molecule consisting of a sonosensitizer protoporphyrin IX (PpIX) and an afterglow substrate that is dual-locked with a H2S-responsive 2,4-dinitrobenzene group and a 1O2-responsive electron-rich double bond. When employing DPA-H2S for imaging of MET-induced liver injury in vivo, since the PpIX moiety can produce 1O2in situat the liver site under focused ultrasound (US) irradiation, the two locks of DPA-H2S can be specifically activated by the highly upregulated H2S at the liver injury sites and the in situgenerated 1O2, respectively. Thus, the sonoafterglow signal of DPA-H2S is significantly turned on, enabling precise imaging of the MET-induced liver injury. In vitroresults showed that, through H2S-activated sonoafterglow luminescence, DPA-H2S was capable of imaging H2S with good sensitivity and high selectivity and realized deep tissue imaging (∼20 mm, signal-to-background ratio (SBR) = 3.4). Furthermore, we successfully applied DPA-H2S for precise in vivoimaging of MET-induced liver injury. We anticipate that our dual-locked probe, DPA-H2S, may serve as a promising tool in assisting the diagnosis of MET-induced liver injury in clinics and informing the clinical utilization of MET in the near future.

Efficient energy transfer is a promising strategy in overcoming the inherent limits of a narrow band and weak absorption of lanthanide ions due to the nature of 4f–4f transitions. Herein, we introduce a nanoparticle-sensitized nanoparticle system where a near-infrared-emitting quantum dot (QD) is used as a sensitizer with broadband photon absorption for a lanthanide-doped nanoparticle (LNP) to generate second near-infrared (NIR-II) emission. The NIR-II luminescence of Er3+-doped LNP by Ag2S QD sensitization displays an enhancement of ∼17-fold in intensity and ∼10-fold in brightness over bare LNP because of increased absorptivity and overall broadening of the absorption spectrum of LNP. Furthermore, a QD-sensitized LNP system exhibits excellent photostability and is able to improve the signal-to-noise ratio of tumor NIR-II imaging viain situcross-linking of QD and LNP. The QD-sensitized LNP system for luminescence enhancement opens a potential avenue for efficient energy transfer in complex nanoparticle–nanoparticle systems.

As key characteristic molecules, several H2S-activated probes have been explored for colon cancer studies. However, a few ratiometric fluorescence (FL) probes with NIR-II emissions have been reported for the quantitative detection of H2S in colon cancer in vivo. Here, we developed an in situH2S-activatable ratiometric nanoprobe with two NIR-II emission signals for the detection of H2S and intelligently lighting up colon cancer. The nanoprobe comprised a down conversion nanoparticle (DCNP), which emitted NIR-II FL at 1550 nm on irradiation with a 980 nm laser (F1550Em, 980Ex). Further, human serum albumin (HSA) was combined with Ag+on the surface of DCNP to form a DCNP@HSA-Ag+nanoprobe. In the presence of H2S, Ag2S quantum dots (QDs) were formed in coated HSA, which emitted FL at approximately 1050 nm on irradiation with an 808 nm laser (F1050Em, 808Ex) through an H2S-induced chemical reaction between H2S and Ag+; however, the FL signal of DCNP was stable at 1550 nm (F1550Em, 980Ex), generating a H2S concentration-dependent ratiometric F1050Em, 808Ex/F1550Em, 980Exsignal. The NIR-II ratiometric nanoprobe was successfully used for the accurate quantitative detection of H2S and the detection of the precise location of colon cancer through an endogenous H2S-induced in situreduction reaction to form Ag2S QDs. Thus, these findings provide a new strategy for the specific detection of targeted molecules and diagnosis of disease based on the in situ-activatable NIR-II ratiometric FL nanoprobe.