Ultra-thin solid-state nanopore with good wetting property is strongly desired to achieve high spatial resolution for DNA sequencing applications. Atomic thick hexagonal boron nitride (h-BN) layer provides a promising two-dimensional material for fabricating solid-state nanopores. Due to its good oxidation resistance, the hydrophilicity of h-BN nanopore device can be significantly improved by UV-Ozone treatment. The contact angle of a KCl-TE droplet on h-BN layer can be reduced from 57° to 26° after the treatment. Abundant DNA translocation events have been observed in such devices, and strong DNA-nanopore interaction has been revealed in pores smaller than 10 nm in diameter. The 1/f noise level is closely related to the area of suspended h-BN layer, and it is significantly reduced in smaller supporting window. The demonstrated performance in h-BN nanopore paves the way towards base discrimination in a single DNA molecule.

Tumors are usually hypoxic, which limits the efficacy of current tumor therapies, especially radiotherapy in which oxygen is essential to promote radiation-induced cell damage. Herein, by taking advantage of the ability of perfluorocarbon (PFC) to promote red blood cell penetration, we developed a simple but effective two-stage oxygen delivery strategy to modulate the hypoxic tumor microenvironment using PFC nanoparticles.Methods: We first examined the two-stage oxygen delivery ability of PFC nanoparticles on relieving tumor hypoxia through platelet inhibition. To evaluate the effect of PFC nanoparticles on radiation sensitization, CT26 tumor and SUM49PT tumor model were used.Results: In this study, PFC was encapsulated into albumin and intravenously injected into tumor-bearing mice without hyperoxic breathing. After accumulation in the tumor, PFC nanoparticles rapidly released the oxygen that was physically dissolved in PFC as the first-stage of oxygen delivery. Then, PFC subsequently promoted red blood cell infiltration, which further released O2 as the second-stage of oxygen delivery.Conclusion: The hypoxic tumor microenvironment was rapidly relieved via two-stage oxygen delivery, effectively increasing radiotherapy efficacy. The safety of all substances used in this study has been clinically demonstrated, ensuring that this simple strategy could be rapidly and easily translated into clinical applications to solve the clinical problems associated with tumor hypoxia.

Photodynamic therapy (PDT) is a promising strategy for cancer treatment. It can not only generate reactive oxygen species (ROS) to cause the chemical damage of tumor cells in the presence of enough oxygen but also promote the antitumor immunity of T cells through enhancing the production of interferon γ (IFN-γ). However, one phenomenon is ignored so far that the enhanced production of IFN-γ caused by PDT may significantly increase the expression of programmed death-ligand 1 (PD-L1) on the tumor cell membrane and thus could inhibit the immune killing effects of T cells. Herein, we report the construction of a composite by loading metformin (Met) and IR775 into a clinically usable liposome as a two-in-one nanoplatform (IR775@Met@Lip) to solve this problem. The IR775@Met@Lip could reverse tumor hypoxia to enhance ROS production to elicit more chemical damage. Besides, the overexpression of PD-L1 by PDT was also effectively down-regulated. These therapeutic benefits including decreased PD-L1 expression, alleviated T cell exhaustion, and reversed tumor hypoxia successfully suppressed both the primary and abscopal tumor growth in bladder and colon cancers, respectively. Combining with its excellent biocompatibility, our results indicate that this IR775@Met@Lip system has great potential to become a highly effective cancer therapy modality.

Currently, limited tumor drug permeation and poor oxygen perfusion are two major bottlenecks that significantly impair the efficacy of existing antitumor drugs, especially oxygen‐sensitive antitumor drugs. One vital cause of these major bottlenecks is the abnormal tumor vessel barrier. To the best knowledge of the authors, platelets play a vital role in the maintenance of an abnormal tumor blood barrier through platelet–tumor interaction. Thus, platelet inhibition may present a new way to enhance drug delivery. In this study, it is originally discovered that perfluorotributylamine‐based albumin nanoparticles (PFTBA@HSA) possess excellent platelet inhibiting abilities, which then selectively disrupt the tumor vessel barrier, resulting in a remarkably enhanced intratumoral drug accumulation. Interestingly enough, the tumor hypoxia is also obviously relieved by enhanced oxygen carrier red blood cell distribution and PFTBA@HSA infiltration in the tumors. Finally, the efficacy of oxygen‐sensitive antitumor drugs is significantly amplified by PFTBA@HSA owing to enhanced drug permeation and relieved tumor hypoxia. Therefore, for the first time, it is demonstrated that PFTBA@HSA could be used as an effective way to improve the efficacy of existing tumor therapies by disrupting tumor vessel barriers through targeted platelet inhibition.

programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) axis regulation has presented impressive therapeutic efficacy against multiple types of cancers by enhancing T cell infiltration and revitalizing exhausted cytotoxic T cells, which finally shifted the paradigm of cancer management. [1] However, although the current clinically approved and used anti-PD-L1 monoclonal antibodies are effective in the treatment of many cancer types, their widespread usage is still limited and risky owing to immune-related adverse effects, insufficient tumor specificity, and high cost. [2] Moreover, most anti-PD-L1 monoclonal antibodies could only disrupt the PD-1/ PD-L1 axis recognition on the surfaces of T cells and cancer cells, without taking into account the immune-regulation capacity of the cytoplasm or the nucleus distributed PD-L1 protein, which also seriously limited the efficacy of radioimmunotherapy and chemoimmunotherapy when combined with anti-PD-L1 monoclonal antibodies since anti-PD-L1 monoclonal antibodies could not influence the cytoplasm or the nucleus distributed PD-L1 protein and its mediated increased DNA damage repair. [3] Thus, there is still a need to better understand the mechanisms of regulating the PD-L1/PD-1 axis to augment approaches that target this pathway.Currently, the role of the lysosome, endoplasmic reticulum, or dictyosome in the transcription and translation of programmed cell death ligand 1 (PD-L1) is well revealed, but the role and function of mitochondria in the PD-L1 expression in tumors is still not fully researched, making it hard to offer a novel PD-L1 regulation strategy. In this research, it is newly revealed that mitochondria oxidative phosphorylation (OXPHOS) depression can be used as an effective PD-L1 down-regulation method. To offer an ideal and higheffective tumor mitochondria-targeted OXPHOS depression nanosystem, IR-LND is prepared by conjugating mitochondria-targeted heptamethine cyanine dye IR-68 with mitochondrial complexes I and II depression agent lonidamine (LND), which then further self-assembled with albumin (Alb) to form IR-LND@Alb nanoparticles. By doing this, PD-L1 expression in tumors is selectively and effectively depressed by IR-LND@Alb nanoparticles. As expected, the anti-tumor efficacy of such a PD-L1 depression strategy is superior to conventional anti-PD-L1 monoclonal antibodies. Interestingly, IR-LND can also be served as a novel ideal promising photodynamic therapy (PDT) drug with self-oxygen and self-PD-L1 regulation capacity. All in all, this tumorselective metabolic reprogramming platform to reactivate immunotherapy and sensitize for PDT effect, would open a new window for mitochondrial immunotherapy for cancer patients.

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Nanopore technology has become a highly sensitive and powerful tool for single molecule sensing of chemicals and biopolymers. Protein pores have the advantages of size amenability, channel homogeneity, and fabrication reproducibility. But most well-studied protein pores for sensing are too small for passage of peptide analytes that are typically a few nanometers in dimension. The funnel-shaped channel of bacteriophage phi29 DNA packaging motor has previously been inserted into a lipid membrane to serve as a larger pore with a narrowest N-terminal constriction of 3.6 nm and a wider C-terminal end of 6 nm. Here, the utility of phi29 motor channel for fingerprinting of various peptides using single molecule electrophysiological assays is reported. The translocation of peptides is proved unequivocally by single molecule fluorescence imaging. Current blockage percentage and distinctive current signatures are used to distinguish peptides with high confidence. Each peptide generated one or two distinct current blockage peaks, serving as typical fingerprint for each peptide. The oligomeric states of peptides can also be studied in real time at single molecule level. The results demonstrate the potential for further development of phi29 motor channel for detection of disease associated peptide biomarkers.