Vascular disrupting agents (VDAs) can destroy tumor vasculature and lead to tumor ischemia and hypoxia, resulting in tumor necrosis. However, VDAs are easy to induce the upregulation of genes that are associated with drug resistance and angiogenesis in tumor cells. Hypoxia-activated chemotherapy will be an ideal supplement to VDAs therapy since it can help to fully utilize the ischemia and hypoxia induced by VDAs to realize a synergistic antitumor therapeutic outcome. Here, we design a liposome whose surface is modified with a tumor-homing peptide Cys-Arg-Glu-Lys-Ala (CREKA, which can specifically target tumor vessels and stroma) and whose inner cavity is loaded by a hypoxia-activated drug banoxantrone dihydrochloride (AQ4N) as well as a VDA combretastatin A4 (CA4). CA4 can selectively target vascular endothelial cells and destroy the tumor blood vessels, which will cause the rapid closure of blood flow in tumor and enhance the hypoxia in the tumor region. As a consequence, AQ4N can exert its boosted cytotoxicity under the enhanced hypoxic environment. The as-prepared liposome with a uniform particle size exhibits good stability and high cancer cell killing efficacy in vitro. In addition, in vivo experiments confirm the excellent tumor-targeting/accumulation, tumor vascular damaging, and tumor inhibition effects of the liposome. This work develops CA-TL which can achieve safe and effective tumor suppression without external stimulus excitation by only single injection, and is expected to benefit the future development of effective antitumor liposomal drugs.

Table S2 Lists antibodies used in western blot, immunofluorescence and Flow cytometry.

The existence of a delicate redox balance in tumors usually leads to cancer treatment failure. Breaking redox homeostasis by amplifying oxidative stress and reducing glutathione (GSH) can accelerate cancer cell death. Herein, we construct a ferroptosis-reinforced nanocatalyst (denoted as HBGL) to amplify intracellular oxidative stress via dual H2O2 production-assisted chemodynamic therapy (CDT). Specifically, a long-circulating liposome is employed to deliver hemin (a natural iron-containing substrate for Fenton reaction and ferroptosis), β-lapachone (a DNA topoisomerase inhibitor with H2O2 generation capacity for chemotherapy), and glucose oxidase (which can consume glucose for starvation therapy and generate H2O2). HBGL can achieve rapid, continuous, and massive H2O2 and •OH production and GSH depletion in cancer cells, resulting in increased intracellular oxidative stress. Additionally, hemin can reinforce the ferroptosis-inducing ability of HBGL, which is reflected in the downregulation of glutathione peroxidase-4 and the accumulation of lipid peroxide. Notably, HBGL can disrupt endo/lysosomes and impair mitochondrial function in cancer cells. HBGL exhibits effective tumor-killing ability without eliciting obvious side effects, indicating its clinical translation potential for synergistic starvation therapy, chemotherapy, ferroptosis therapy, and CDT. Overall, this nanocatalytic liposome may be a promising candidate for achieving potentiated cancer treatment.

Supplementary Figure S7 shows that MIF is associated with immunosuppressive Tumor microenvironment.

The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment. A glucose oxidase (GOx)-, dc-IR825-, and sorafenib-containing liposome is designed for triple energy depletion-based tumor therapy. GOx continuously consumes glucose in the tumor. dc-IR825 precisely targets and destroys mitochondria upon laser irradiation. Sorafenib inhibits tumor vessel growth to block energy and nutrition supply from blood. Such a multifaceted liposome can effectively exhaust energy in a tumor and starve the tumor to death. image

Table S1 shows the sequences of sgRNAs, shRNAs and primers for cloning and qRT-PCR analysis.

Supplementary Figure S5 shows that MIF promotes cancer cell proliferation, migration and invasion.

The largest obstacle that impedes the successful clinical use of anticancer nanodrugs lies in their unsatisfactory therapeutic performance even if multiple drug treatments are applied, which may cause tumor relapse and drug resistance. Therefore, it is challenging to develop effective nanodrugs that can eradicate tumors with only single injection. Herein, we construct a metabolic nanomodulator (denoted as ISM liposome), where the phototherapeutic dye IR825-NH2, the chemodrug shikonin, and the mitochondrial respiration inhibitor metformin are encapsulated, to closely synergize phototherapy, chemotherapy, and immunotherapy via the laser-triggered on-demand metabolism regulation for realizing robust anticancer potency after only single injection and irradiation. Upon near-infrared laser irradiation, IR825-NH2 can generate reactive oxygen species and mild heat to enable the phototherapeutic cytotoxcity and thermoresponsive release of the loaded drugs. Then, cellular oxygen can be spared by the released metformin via metabolic modulation and be utilized by shikonin to further amplify the oxidative stress in cancer cells. More importantly, the ISM liposome-mediated photochemotherapy can subsequently elicit a strong immunogenic cell death (ICD) effect and sensitize the immunosupressive tumor to the ICD-induced immunotherapy, thereby achieving strong tumor inhibition and even eradication. The metabolic nanomodulator-based photochemotherapy-sensitized cancer immunotherapy may represent a new solution to fight against cancer.

One of the challenges posed by current antibacterial therapy is that the expanded and massive use of antibiotics endows bacteria with the ability to resist almost all kinds of antibiotics. Therefore, developing alternative strategies for efficient antibacterial treatment is urgently needed. Antibacterial gas therapy has attracted much attention in the past decade. Nitric oxide (NO), carbon monoxide (CO), sulfur dioxide (SO2), hydrogen sulfide (H2S), and hydrogen (H2) are not only known as endogenous signaling molecules, but also play critical roles in many pathological processes. These gases are considered as attractive bactericidal agents because they are able to kill bacteria, disperse biofilms, and promote bacteria-infected wound healing while avoiding resistance. In this review, we discuss the bactericidal properties of these gases, as well as the recent advances of gas-involving systems in antibacterial, antibiofilm, and wound treatment applications. Moreover, we summarize various gas donors utilized in antibacterial treatment. We hope this review will shed new light on the future design and applications of advanced antibacterial gas therapy.

Metal whisker growth poses a significant reliability threat to electronic devices. Previous investigations have predominantly focused on metal platings and alloy solder samples, yet the intricate factors involved have yielded inconsistent comprehension of the phenomenon. To achieve a comprehensive understanding, exploring intermetallic compounds (IMCs) may offer a novel standpoint. Herein, we present the first report on the growth of single crystal cadmium (Cd) whiskers on Ti2Cd IMC, accompanied by the characterization of their composition, crystal structure, and morphological features. Furthermore, the influence of mechan ical damage and temperature on the whisker growth is examined. Ball milling induces the decomposition of Ti2Cd, liberating active Cd atoms with elevated chemical potentials that consequently feed the whisker growth. These findings augment the existing knowledge on the topic of the metal whisker growth and provide fresh perspectives and references for further investigations in this field.

Multifunctional nanoparticles (NPs) with simultaneous multimodal therapeutic and imaging capabilities are very necessary for biomedical applications. We successfully prepared bowl-shaped gold@polydopamine yolk-shell NPs (bowl-shaped Au@PDA YNPs) by a novel and facile method. The unique bowl-like structure enables a drug loading rate of 92% (920 μg mg-1). The bowl-shaped Au@PDA YNPs are biocompatible, have good photothermal conversion and strong near-infrared (NIR) absorption, and can control drug release under pH/NIR dual response. Bowl-shaped Au@PDA YNPs can also be employed as contrast agents for computed tomography/photoacoustic imaging for dual-modal imaging-guided chemotherapy and photothermal therapy due to the presence of Au NPs.

Given the significant impact of ions on environment pollution and human health, it is urgently needed to establish effective and convenient ion detection approaches, particularly in living cells. In this paper, we con-structed multicolor N-doped-carbon dots (mPD-CDs) by facile one-step hydrothermal carbonization of m-phe-nylenediamine (mPD). mPD-CDs were successfully deployed for multicolor cellular imaging for animal cells, fungi, and bacteria in a wash-free way with high photostability and satisfactory biocompability. Moreover, mPD-CDs can be used as a fluorescent sensing probe for ultrasensitive detection of both iodide ion (I-) and typical heavy metals such as cadmium (Cd2+), copper (Cu2+), mercury (Hg2+), gadolinium (Gd3+), ferrous ion (Fe2+), Zinc (Zn2+), and ferric ion (Fe3+). This is the first report using CDs as optical sensing probe for the detection of Gd3+, and for detection of Fe3+ with fluorescence "turn on ". More significantly, with these versatile and fasci-nating properties, we applied mPD-CDs for intracellular ion detection in living cells like Hep G2 and S. cerevisiae, and zebra fish. Altogether, mPD-CDs displayed great potential for multicolor cell imaging and the multiple ion detection in vitro and in vivo, presenting a promising strategy for in-situ ultrasensitive sensing of multiple metal ions in the environment and the biological systems.

Recent years have witnessed the rapid development of the biomimetic nanotechnology regarding the use of certain components (such as cell membranes, extracellular vesicles, proteins, etc.) derived from different cells to fabricate nanoparticles (NPs) for cancer treatment. These biomimetic NPs usually inherit certain abilities from their parental cells, such as long blood circulation, capacity to escape from mononuclear phagocytic system, active tumor-targeting, and controlled drug release. Immunocytes play vital roles in different tumor progression stages, and can quickly and accurately react to tumor progression via specific targeting and immune surveillance. Therefore, increasing studies focus on constructing biomimetic NPs with components isolated from immunocytes. This review introduces four main types of immunocyte-derived nanodrugs-membrane-coated NPs, exosomes or extracellular vesicles, functional protein-incorporated NPs, and exosome mimetics-and summarizes the recent advances of these nanodrugs for cancer therapy. Some current challenges and future research directions of immunocyte-derived nanodrugs are also proposed. It is hoped that this review may help researchers in the related field to design new immunocyte-derived nanomedicines and promote their preclinical and clinical applications in the near future.

BACKGROUND:Cytochrome P450 3A5 (CYP3A5) includes two active genotypes, namely CYP3A5*1/*1 or *1/*3 with the fast metabolic activity and CYP3A5*3/*3 with slow metabolic. We retrospectively analyzed the correlation between CYP3A5 gene polymorphism and the susceptibility to the BK virus (BKV) infection in renal transplant recipients. METHODS:According to the inclusion/ exclusion criteria, we selected 134 recipients who received kidney transplantation at the Renmin Hospital of Wuhan University from January 2019 to December 2019. Based on the pre-operative CYP3A5 sequencing results, 134 recipients were divided into two groups: those expressing the fast metabolic CYP3A5*1/*1 or *1/*3 genotype; and, those expressing slow metabolic CYP3A5*3/*3 genotype. These two recipient groups were then analyzed for the BKV infection rate with different metabolic types to establish the potential relationship between CYP3A5 gene polymorphism and BKV infection. RESULTS:The overall incidence of BKV viruria was 37.3%, whereas BKV viremia was 4.5% among all 134 recipients. The fast metabolism group had 9.1% incidence of BKV viremia and 49.1% incidence of BKV viruria. In contrast, the slow metabolism group had only 1.3%incidence of BKV viremia (P = 0.031) with only 29.1% BKV viruria (P = 0.011). The incidence of low levels of urinary BKV in the fast metabolism group was higher than that in the slow metabolism group (P = 0.005), while no significant statistical difference in the incidence of high levels of urinary BKV and high and low levels of blood BKV. CONCLUSION:After kidney transplantation, CYP3A5 gene polymorphism of recipients present a certain relationship with the occurrence of BKV infection, which may be of value for the prediction and prevention of BKV infection.

Rapid and accurate differentiation between live and dead cells is highly desirable for the evaluation of cell viability. Here, we report the application of the orange-emitting sulfur-doped organosilica nanodots (S-OSiNDs) for ultrafast (30 s), ultrasensitive (1 μg/mL), and universal staining of the dead bacterial, fungal, and mammalian cells but not the live ones, which satisfies the requirements of a fluorescent probe that can specifically stain the dead cells. We further verify that the fluorescence distribution range of S-OSiNDs (which are distributed in cytoplasm and nucleus) is much larger than that of the commercial dead/fixed cell/tissue staining dye RedDot2 (which is distributed in the nucleus) in terms of dead mammalian cell staining, indicating that S-OSiNDs possess a better staining effect of dead cells than RedDot2. Overall, S-OSiNDs can be used as a robust fluorescent probe for ultrafast and accurate discrimination between dead and live cells at a single cell level, which may find a variety of applications in the biomedical field.