The common drawbacks of current colorimetric sensors using gold nanoparticle aggregation is its relatively low sensitivity and narrow dynamic range, which restrict their application in real sample analysis when competing with other analytical techniques such as fluorescence and chemiluminescence. In this article, we demonstrate a novel strategy to construct colorimetric sensors based on gold nanoparticle aggregation. Unlike the conventional colorimetric sensors which cause the formation of large nanoparticle aggregates, in our strategy, dimers are selectively formed upon target binding, which results in significantly improved long-term stability and a more than 2 orders of magnitude wider dynamic range of detection than that of the conventional colorimetric sensors. In addition, a strategy to minimize the interparticle gap through the formation of a Y-shaped DNA duplex enables to increase the limit of detection by 10,000 times. The analytical figures of merit of the proposed sensor are comparable to those of the fluorescence-based sensors.

The capability of monitoring the differentiation process in living stem cells is crucial to the understanding of stem cell biology and the practical application of stem-cell-based therapies, yet conventional methods for the analysis of biomarkers related to differentiation require a large number of cells as well as cell lysis. Such requirements lead to the unavoidable loss of cell sources and preclude real-time monitoring of cellular events. In this work, we report the detection of microRNAs (miRNAs) in living human mesenchymal stem cells (hMSCs) by using polydopamine-coated gold nanoparticles (Au@PDA NPs). The PDA shell facilitates the immobilization of fluorescently labeled hairpin DNA strands (hpDNAs) that can recognize specific miRNA targets. The gold core and PDA shell quench the fluorescence of the immobilized hpDNAs, and subsequent binding of the hpDNAs to the target miRNAs leads to their dissociation from Au@PDA NPs and the recovery of fluorescence signals. Remarkably, these Au@PDA-hpDNA nanoprobes can naturally enter stem cells, which are known for their poor transfection efficiency, without the aid of transfection agents. Upon cellular uptake of these nanoprobes, we observe intense and time-dependent fluorescence responses from two important osteogenic marker miRNAs, namely, miR-29b and miR-31, only in hMSCs undergoing osteogenic differentiation and living primary osteoblasts but not in undifferentiated hMSCs and 3T3 fibroblasts. Strikingly, our nanoprobes can afford long-term tracking of miRNAs (5 days) in the differentiating hMSCs without the need of continuously replenishing cell culture medium with fresh nanoprobes. Our results demonstrate the capability of our Au@PDA-hpDNA nanoprobes for monitoring the differentiation status of hMSCs (i.e., differentiating versus undifferentiated) via the detection of specific miRNAs in living stem cells. Our nanoprobes show great promise in the investigation of the long-term dynamics of stem cell differentiation, identification and isolation of specific cell types, and high-throughput drug screening.

The overall response rate for anti-PD-1 therapy remains modest in hepatocellular carcinoma (HCC). We found that a combination of interferon alpha (IFN-a) and anti-PD-1-based immunotherapy resulted in enhanced antitumor activity in unresectable HCC patients. In both immunocompetent orthotopic and spontaneous HCC models, IFN-a therapy synergized with anti-PD-1 and the combination treatment led to significant enrichment of cytotoxic CD27+ CD8+ T cells. Mechanistically, IFN-a suppressed HIF1a signaling by inhibiting FosB transcription in HCC cells, resulting in reduced glucose consumption capacity and consequentially establishing the high-glucose microenvironment that fostered transcription of the T cell costimulatory molecule Cd27 via mTOR-FOXM1 signaling in infiltrating CD8+ T cells. Together, these data reveal that IFN-a reprograms glucose metabolism within HCC tumor microenvironment, thereby liberating T cell cytotoxic capacities and potentiating the PD-1 blockade-induced immune response. Our findings suggest that IFN-a and anti-PD-1 cotreatment is an effective novel combination strategy for HCC patients.

Mussel adhesion has inspired the development of catechol-based adhesive polymers. However, conventional strategies require basic pH conditions and lead to the loss of adhesion. To solve the problem, we report the first attempt to use thiourea-functionalized polymers for preserving hydrogel adhesion. We believe that this simple thiourea-quinone coupling chemistry is instrumental to synthetic adhesive materials.