Role of long non-coding RNAs in cancer: From subcellular localization to nanoparticle-mediated targeted regulation.

Long non-coding RNAs (lncRNAs) are a class of RNA transcripts more than 200 nucleotides in length that play crucial roles in cancer development and progression. With the rapid development of high-throughput sequencing technology, a considerable number of lncRNAs have been identified as novel biomarkers for predicting the prognosis of cancer patients and/or therapeutic targets for cancer therapy. In recent years, increasing evidence has shown that the biological functions and regulatory mechanisms of lncRNAs are closely associated with their subcellular localization. More importantly, based on the important roles of lncRNAs in regulating cancer progression (e.g., growth, therapeutic resistance, and metastasis) and the specific ability of nucleic acids (e.g., siRNA, mRNA, and DNA) to regulate the expression of any target genes, much effort has been exerted recently to develop nanoparticle (NP)-based nucleic acid delivery systems for in vivo regulation of lncRNA expression and cancer therapy. In this review, we introduce the subcellular localization and regulatory mechanisms of various functional lncRNAs in cancer and systemically summarize the recent development of NP-mediated nucleic acid delivery for targeted regulation of lncRNA expression and effective cancer therapy.

Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)-Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to Sorafenib.

Tyrosine kinase inhibitors represented by sorafenib are the first-line treatment for hepatocellular carcinoma (HCC), but the low response rate of HCC patient has become a clinical pain-point. Emerging evidences have revealed that metabolic reprogramming plays an important role in regulating the sensitivity of tumor cells to various chemotherapeutics including sorafenib. However, the underlying mechanisms are very complex and are not fully elucidated. By comparing the transcriptome sequencing data of sorafenib-sensitive and -insensitive HCC patients, it is revealed that cofilin 1 (CFL1) is highly expressed in the tumor tissues of sorafenib-insensitive HCC patients and closely correlated with their poor prognosis. Mechanically, CFL1 can promote phosphoglycerate dehydrogenase transcription and enhance serine synthesis and metabolism to accelerate the production of antioxidants for scavenging the excessive reactive oxygen species induced by sorafenib, thereby impairing the sorafenib sensitivity of HCC. To translate this finding and consider the severe side effects of sorafenib, a reduction-responsive nanoplatform for systemic co-delivery of CFL1 siRNA (siCFL1) and sorafenib is further developed, and its high efficacy in inhibiting HCC tumor growth without apparent toxicity is demonstrated. These results indicate that nanoparticles-mediated co-delivery of siCFL1 and sorafenib can be a new strategy for the treatment of advanced HCC.

Iridium/ruthenium nanozyme reactors with cascade catalytic ability for synergistic oxidation therapy and starvation therapy in the treatment of breast cancer.

The application of nanozymes to specifically treat tumors in the tumor microenvironment (TME) would be a novel and effective strategy. Here, ultra-small IrRu alloy nanoparticles (IrRu NPs) with dual enzyme activities were synthesized by a simple method. PEG surface modification was carried out to improve the biocompatibility of nanoparticles. Meanwhile, the natural enzyme glucose oxidase (GOx) was loaded to synthesize a multi-enzyme nanoreactor (IrRu-GOx@PEG NPs) that could undergo cascade catalytic reaction. In the first catalytic stage, GOx in IrRu-GOx@PEG NPs degraded tumor tissue-sensitive glucose to hydrogen peroxide (H2O2), which cut off the nutrient source of the tumor and inhibited tumor growth by starvation therapy. In the second catalytic stage, IrRu NPs in IrRu-GOx@PEG NPs catalyzed the upstream endogenous H2O2 to highly toxic singlet oxygen 1O2 and O2. Among them, 1O2 could directly induce apoptosis of cancer cells by the oxidative therapy, and O2 could resolve the problem of hypoxia that easily led to the termination of the starvation therapy response in tumor microenvironment, thereby making the cycle of starvation therapy-related reactions continue to occur. It also inhibited the metastasis of tumors caused by hypoxia. In vitro catalytic activity studies showed that IrRu-GOx@PEG NPs had good and stable catalytic activity and could effectively induce apoptosis of 4T1 cancer cells. In addition, in vivo results further demonstrated that IrRu-GOx@PEG NPs could effectively treat breast cancer in combination with starvation therapy and oxidative therapy. This treatment strategy is expected to be used in the treatment of other cancers, bringing new treatment strategies for cancer treatment.

Responsive functionalized MoSe2 nanosystem for highly efficient synergistic therapy of breast cancer.

The photothermal/photodynamic synergistic therapy is a promising tumor treatment, but developing nanosystems that achieve synchronous photothermal/photodynamic functions is still quite challenging. Here, we use a simple method to synthesize molybdenum selenide nanoparticles (MoSe2 NPs) with a photothermal effect as a carrier, and load a photosensitizer ICG to form a nanosystem (MoSe2@ICG-PDA-HA)with dual photothermal/photodynamic functions under near-infrared irradiation. In addition, the surface modification of the nanosystem with acid-responsive release polydopamine (PDA) and tumor-targeted hyaluronic acid (HA) enhanced the stability of the photosensitizer ICG and the accumulation of ICG at tumor sites. The multicellular sphere assay simulated solid tumors and demonstrated that MoSe2@ICG-PDA-HA could significantly inhibit the 4T1 cell growth. The anti-tumor experiments in tumor-bearing mice showed that MoSe2@ICG-PDA-HA not only significantly inhibited the growth of 4T1 subcutaneous tumors, but also inhibited their metastasis. This study presented a nanosystem that could improve the photostability of optical materials and enhance the photothermal/photodynamic synergy effect, providing a new idea for finding a way to effectively treat breast cancer.

Hollow mesoporous ruthenium nanoparticles conjugated bispecific antibody for targeted anti-colorectal cancer response of combination therapy.

Combined treatment based on tumor-targeted nanoparticles has become one of the most promising anticancer strategies. Moreover, bispecific antibodies have been designed as linkers to promote the interaction between natural killer (NK) cells and tumor cells, while triggering NK cell-mediated target cell lysis. Here, we adopted a novel design that uses PEGylated hollow mesoporous ruthenium nanoparticles as a carrier to load the fluorescent anti-tumor complex ([Ru(bpy)2(tip)]2+, RBT) and a conjugate with bispecific antibodies (SS-Fc). By accurately targeting carcinoembryonic antigen overexpressed in colorectal cancer cells, HMRu@RBT-SS-Fc significantly improved selective penetration in vitro. The functionalized nanocomplex effectively engaged NK cells and possessed excellent near infrared-sensitive cytotoxicity. Systematic in vivo studies clearly demonstrated the high tumor targeting and anticancer activity in heterotopic colorectal tumor model via combined photothermal and immune therapy. This nanosystem establishes a new platform for future image-guided drug delivery and highly efficient cancer therapy.

Drug Delivery System Based on Near-Infrared Light-Responsive Molybdenum Disulfide Nanosheets Controls the High-Efficiency Release of Dexamethasone To Inhibit Inflammation and Treat Osteoarthritis.

Intra-articular injection has unique advantages in the treatment of osteoarthritis (OA), although it risks rapid clearance of the therapeutic drugs in the joint cavity. Combining therapeutic agents with functionalized nanocarriers may provide an effective solution. Controlling the therapeutic concentration of the drug in the joint cavity through the drug-loading nanosystem can synergistically treat OA. Here, we proposed an intra-articular drug delivery nanosystem MoS2@CS@Dex (MCD), using the chitosan (CS)-modified molybdenum disulfide (MoS2) nanosheets as near-infrared (NIR) photo-responsive carriers, loaded with the anti-inflammatory drug dexamethasone (Dex). MCD responded to NIR light both in vitro and in vivo and triggered Dex release through photothermal conversion. This enabled the remote-controlled Dex release in the joint cavity by adjusting the radiation behavior of the NIR light. MCD prolonged the residence time of Dex in the joint cavity. The intra-articular injection of MCD in combination with NIR radiation ensured a significant increase in the therapeutic effect of Dex at low systemic doses, which attenuated the cartilage erosion in the OA caused by the secretion of inflammatory factors including TNF-α and IL-1ß. The toxicity and side effects on other internal organs during metabolism were reduced in the body. In addition, the photoacoustic imaging capability of MoS2 nanosheets was used to detect the metabolism of MCD in the joint cavity. Our research indicated that MCD has great potential to treat OA.

Progressive release of mesoporous nano-selenium delivery system for the multi-channel synergistic treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with a complex pathogenesis. Controlled release, target ability, and multi-channel synergistic treatment are key factors associated with the success of AD drugs. Herein, we report a novel mesoporous nano-selenium (MSe) release delivery system (MSe-Res/Fc-ß-CD/Bor) based on the borneol (Bor) target, ß-cyclodextrin nanovalves (Fc-ß-CD) with loaded resveratrol (Res). Previous experiments have shown that MSe-Res/Fc-ß-CD/Bor first releases Bor by interacting with blood or intracellular esterases, allowing the nanosystem to pass through the blood-brain barrier (BBB). Subsequently, the Fc-ß-CD is opened by the redox (H2O2) response to the release of Res at the lesion site. We demonstrated that MSe-Res/Fc-ß-CD/Bor inhibited aggregation of ß-amyloid proteins (Aß), mitigated oxidative stress, and suppressed tau hyperphosphorylation, while protecting nerve cells and successfully improving memory impairment in APP/PS1 mice. Interestingly, compared with rivastigmine (Riv) positive drugs alone, the MSe/Fc-ß-CD/Bor loaded with Riv had a better pharmacokinetic index. These results indicate that MSe-Res/Fc-ß-CD/Bor could be a prospective drug for treating AD.

Correction: Flower-like gold nanoparticles for enhanced photothermal anticancer therapy by the delivery of pooled siRNA to inhibit heat shock stress response.

Correction for 'Flower-like gold nanoparticles for enhanced photothermal anticancer therapy by the delivery of pooled siRNA to inhibit heat shock stress response' by Yanan Liu et al., J. Mater. Chem. B, 2019, 7, 586-597.

Flower-like gold nanoparticles for enhanced photothermal anticancer therapy by the delivery of pooled siRNA to inhibit heat shock stress response.

Due to the anti-apoptotic effect employed by cells to protect themselves, recent research shows that photothermal therapy (PTT) can lead to heat shock response, thus reducing the effect of treatment on cancer cells. Small interfering RNA (siRNA), as an effective carrier of RNA interference, can silence the expression of heat shock protein, HSPs or BAG3 genes by inhibiting the expression of specific genes, and thereby inhibiting heat shock response and making cancer cells more sensitive to PTT. In this study, flower-like gold nanoparticles were used as a core for a layer-by-layer strategy to produce a safe and biodegradable nanoparticle platform for gene silencing and photothermal therapy. The results showed that when the mass ratio of the GNFs and siRNA was 20 : 1, the loading efficiency was above 90%, which can effectively silence the expression of BAG3 siRNA. We demonstrated that the GNFs-siRNA still had a good photothermal effect after siRNA modification. In vitro, the GNFs-siRNA showed good biocompatibility and effectively tumor killing properties after laser irradiation. Furthermore, the GNFs-siRNA with laser treatment significantly decreased the expression of BAG3 and remarkably inhibited tumor growth in vivo. This nanosystem establishes an optimized platform for future gene delivery and photothermal therapy.

Prognostic evaluation of NANOG and OCT4 expression for posttransplantation hepatocellular carcinoma recurrence.

Postoperative hepatocellular carcinoma (HCC) recurrence and metastasis throw great threaten to its overall survival (OS). This paper focus on exploring the prognostic significance of NANOG and OCT4 expression in HCC recurrence and OS after liver transplantation. Eighty-six patients who meet University of California San Francisco (UCSF) criteria and underwent liver transplantation in Tianjin First Central Hospital between August 2010 and August 2013 were included. Expression of NANOG and OCT4 was determined by immunohistochemistry. The relationships between NANOG and OCT4 expression with tumor recurrence, tumor count, histology stage, lymph node metastasis (LNM) and microvascular invasion (MVI) were explored through the χ2 test and Cox regression analysis. We found that 19/26 and 20/24 patients with positive expression of NANOG and OCT4 relapsed. Combination of NANOG and OCT4 expression was indicated as valuable prognostic signature for HCC recurrence prediction (P < 0.0011). Besides, we identified other key factors with significant correlations with recurrence, such as LNM (P = 0.011) and MVI (P = 0.024). Strikingly, recurrence sites could significantly affect recurrence time (P = 0.0062) and patients with recurrence in transplanted liver have longer recurrence time. In conclusions, we analyzed the relationships between NANOG/OCT4 expression, clinicopathology features, HCC recurrence, and OS after liver transplantation for the first time. Combination of NANOG, OCT4, LNM, histopathological stage, and MVI may be predictor for HCC recurrence posttransplantation. Comprehensive of histopathological stage grade and LNM were considered as prognosis factor for OS after liver transplantation. This should be helpful for treatment method selection for HCC patients after liver transplantation.

Transferrin/aptamer conjugated mesoporous ruthenium nanosystem for redox-controlled and targeted chemo-photodynamic therapy of glioma.

The blood-brain barrier (BBB) and low targeting are major obstacles for the treatment of gliomas. Accordingly, overcoming the BBB and enhancing the targeting of drugs to the glioma area are key to achieving a good therapeutic effect. Here, we have developed the mesoporous ruthenium nanosystem RBT@MRN-SS-Tf/Apt with dual targeting function. Transferrin (Tf) and aptamer AS1411 (Apt) are grafted on the surfaces of mesoporous ruthenium nanoparticles (MRN) with high loading capacity. This is achieved via redox-cleavable disulfide bonds, serving as both a capping agent and a targeting ligand, enabling the effective penetration of the blood-brain barrier and targeting the glioma. In addition, RBT@MRN-SS-Tf/Apt can specifically kill glioma cells in vitro and in vivo. Moreover, anti-tumor drugs [Ru(bpy)2(tip)]2+ (RBT) will produce reactive oxygen species and induce apoptosis of tumor cells under laser irradiation, providing photodynamic therapy (PDT) for the treatment of gliomas, and further prolonging the median survival period. The study shows that this chemical photodynamic therapy nanosystem can be used as an efficient and powerful synergistic system for the treatment of brain tumors and other brain diseases of the central nervous system. STATEMENT OF SIGNIFICANCE: In order to overcome the blood-brain barrier and low targeting, and enhance the anti-glioma activities of nanodrugs. We have developed RBT@MRN-SS-Tf/Apt with dual targeting function. It is achieved release drug via redox-cleavable disulfide bonds, and enable the effective penetration of the blood-brain barrier and targeting the glioma. Moreover, anti-tumor drugs RBT will produce reactive oxygen species and induce apoptosis of tumor cells under laser irradiation, providing photodynamic therapy (PDT) for the treatment of gliomas, and further prolonging the median survival period. Therefore, this chemical photodynamic therapy nanosystem can be used as an efficient and powerful synergistic system for the treatment of brain tumors and other brain diseases of the central nervous system.

Loss of stability: a new look at the physics of cell wall behavior during plant cell growth.

In this article we investigate aspects of turgor-driven plant cell growth within the framework of a model derived from the Eulerian concept of instability. In particular we explore the relationship between cell geometry and cell turgor pressure by extending loss of stability theory to encompass cylindrical cells. Beginning with an analysis of the three-dimensional stress and strain of a cylindrical pressure vessel, we demonstrate that loss of stability is the inevitable result of gradually increasing internal pressure in a cylindrical cell. The turgor pressure predictions based on this model differ from the more traditional viscoelastic or creep-based models in that they incorporate both cell geometry and wall mechanical properties in a single term. To confirm our predicted working turgor pressures, we obtained wall dimensions, elastic moduli, and turgor pressures of sequential internodal cells of intact Chara corallina plants by direct measurement. The results show that turgor pressure predictions based on loss of stability theory fall within the expected physiological range of turgor pressures for this plant. We also studied the effect of varying wall Poisson's ratio nu on extension growth in living cells, showing that while increasing elastic modulus has an understandably negative effect on wall expansion, increasing Poisson's ratio would be expected to accelerate wall expansion.

Loss of stability, pH, and the anisotropic extensibility of Chara cell walls.

We investigated the effects of acid conditions on the extensibility of isolated wall segments from growing Chara corallina cells, providing the first detailed multi-azimuthal description of the anisotropic elastic modulus of the walls. The values of anisotropic modulus were obtained by loading a tensile force on wall ribbons excised from the cell walls along twelve different azimuths, and measuring the resulting elongation of the ribbons. Our study differs from previous studies in which mechanical loading of the wall materials was performed under creep conditions. We used ramp-loading conditions which meet the requirements for Loss of Stability. The results show that whereas a linear relationship between wall extension and log time is typical for creep-based experiments, it is not seen under ramp-loading conditions. To clarify the relative values of the wall moduli, the complete all-around anisotropic modulus is presented in polar coordinates, with the value of longitudinal modulus normalized to one unit. Acid pH enhances the extensibility of the wall materials, especially when medium pH

Loss of stability-a new model for stress relaxation in plant cell walls.

This study addresses the mechanism of wall stress relaxation in growing plant cells. The current viscoelastic model of cell wall relaxation, which dates from the work of Preston, Cleland, Lockhart, and others in the 1960s, has serious shortcomings. It has been shown however that the theory of loss of stability (LOS) can be applied to materials in tension, leading to the conclusion that the relaxation of stresses in the walls of any pressure vessel is rigorously modeled using LOS. We propose that LOS also provides a more appropriate and versatile model of stress relaxation in growing plant cells. We argue that when treated as a manifestation of LOS, the regulation of cell turgor has a rigorous and demonstrable basis in the geometrical and physical properties of the cell wall and the cell's ability to import water. Thus plant cell growth can be regarded as an inherently self-limiting process, tunable by biochemical or structural means. Lastly, despite the current limitations of our model, we apply direct measurement of elastic modulus, wall thickness and cell radius obtained from cylindrical Chara corallina cells to generate an initial calculation of critical pressures in a hypothetical spherical cell with the same material properties.