Distinguishing cancer cells from normal cells through surface receptors is vital for cancer diagnosis and targeted therapy. Metabolic glycoengineering of unnatural sugars provides a powerful tool to manually introduce chemical receptors onto the cell surface; however, cancer-selective labeling still remains a great challenge. Herein we report the design of sugars that can selectively label cancer cells both in vitro and in vivo. Specifically, we inhibit the cell-labeling activity of tetraacetyl-N-azidoacetylmannosamine (Ac4ManAz) by converting its anomeric acetyl group to a caged ether bond that can be selectively cleaved by cancer-overexpressed enzymes and thus enables the overexpression of azido groups on the surface of cancer cells. Histone deacetylase and cathepsin L-responsive acetylated azidomannosamine, one such enzymatically activatable Ac4ManAz analog developed, mediated cancer-selective labeling in vivo, which enhanced tumor accumulation of a dibenzocyclooctyne–doxorubicin conjugate via click chemistry and enabled targeted therapy against LS174T colon cancer, MDA-MB-231 triple-negative breast cancer and 4T1 metastatic breast cancer in mice.

Finding a timely, sensitive, and noninvasive detection method has become an urgent need for asymptomatic early diagnosis of Alzheimer’s disease (AD). MicroRNA-193b (miR-193b) and Aβ42 oligomers (AβO42) in neurogenic exosomes were confirmed to reflect pathological changes in the AD early stage. The combination of two biomarkers is promising for the earlier detection of AD. In this study, a detection system based on the principle of the entropy-driven strand displacement reaction (ESDR) was developed, including a dumbbell detection probe (H), an indicator probe (R), and graphene oxide (GO). In the detection system, the two hairpins of H were opened by the interaction of miR-193b (T1) and AβO42 (T2) with the aptamer. Then R hybridized with H and began to displace T, initiating the next round of ESDR to achieve sensitive detection of T. GO specifically adsorbed free R and quenched the fluorescence, further reducing the intensity of the background signal. Both of these points provided the system with a more sensitive analytical performance. The detection limit of miR-193b was 77 pM and the detection limit of AβO42 was 53 pM. This sensor detected the change of “one increase (AβO42) and one decrease (miR-193b)” in the exosome sample. Additionally, results showed that this detection system could distinguish the model of early AD from the non-AD control, which was sufficient for earlier and more sensitive detection of AD. This strategy has strong specificity, high sensitivity, and easy operation, which provides broad prospects for the early diagnosis of AD.

The poor penetration into deep tumor tissues of nanomedicines could not inhibit the production of lactic acid by deep tumors glycolysis, which leads to the accumulation of lactic acid and...

Cytosolic DNA from pathogens activates the DNA sensor cyclic GMP–AMP (cGAMP) synthase (cGAS) that produces the second messenger, cGAMP. cGAMP triggers a signal cascade leading to type I IFN expression. Host DNA is normally restricted in the cellular compartments of the nucleus and mitochondria. Recent studies have shown that DNA virus infection triggers mitochondrial stress, leading to the release of mitochondrial DNA to the cytosol and activation of cGAS; however, the regulatory mechanism of mitochondrial DNA-mediated cGAS activation is not well elucidated. In this study, we analyzed cGAS protein interactome in mouse RAW264.7 macrophages and found that cGAS interacted with C1QBP. C1QBP predominantly localized in the mitochondria and leaked into the cytosol during DNA virus infection. The leaked C1QBP bound the NTase domain of cGAS and inhibited cGAS enzymatic activity in cells and in vitro. Overexpression of the cytosolic form of C1QBP inhibited cytosolic DNA-elicited innate immune responses and promoted HSV-1 infection. By contrast, deficiency of C1QBP led to the elevated innate immune responses and impaired HSV-1 infection. Taken together, our study suggests that C1QBP is a novel cGAS inhibitor hidden in the mitochondria.

Retinoic acid-inducible gene I (RIG-I) senses viral RNA and instigates an innate immune signaling cascade to induce type I interferon expression. Currently, the regulatory mechanisms controlling RIG-I activation remain to be fully elucidated. Here we show that the FAK family kinase-interacting protein of 200 kDa (FIP200) facilitates RIG-I activation. FIP200 deficiency impaired RIG-I signaling and increased host susceptibility to RNA virus infection. In vivo studies further demonstrated FIP200 knockout mice were more susceptible to RNA virus infection due to the reduced innate immune response. Mechanistic studies revealed that FIP200 competed with the helicase domain of RIG-I for interaction with the two tandem caspase activation and recruitment domains (2CARD), thereby facilitating the release of 2CARD from the suppression status. Furthermore, FIP200 formed a dimer and facilitated 2CARD oligomerization, thereby promoting RIG-I activation. Taken together, our study defines FIP200 as an innate immune signaling molecule that positively regulates RIG-I activation.