Glioblastoma (GBM) is the most common malignant primary brain tumor with a poor prognosis. The current standard treatment regimen represented by temozolomide/radiotherapy has an average survival time ...of 14.6 months, while the 5-year survival rate is still less than 5%. New therapeutics are still highly needed to improve the therapeutic outcome of GBM treatment. The blood-brain barrier (BBB) is the main barrier that prevents therapeutic drugs from reaching the brain. Nanotechnologies that enable drug delivery across the BBB hold great promise for the treatment of GBM. This review summarizes various drug delivery systems used to treat glioma and focuses on their approaches for overcoming the BBB to enhance the accumulation of small molecules, protein and gene drugs, etc. in the brain.
Vaccines can prevent many millions of illnesses against infectious diseases and save numerous lives every year. However, traditional vaccines such as inactivated viral and live attenuated vaccines ...cannot adapt to emerging pandemics due to their time-consuming development. With the global outbreak of the COVID-19 epidemic, the virus continues to evolve and mutate, producing mutants with enhanced transmissibility and virulence; the rapid development of vaccines against such emerging global pandemics becomes more and more critical. In recent years, mRNA vaccines have been of significant interest in combating emerging infectious diseases due to their rapid development and large-scale production advantages. However, their development still suffers from many hurdles such as their safety, cellular delivery, uptake, and response to their manufacturing, logistics, and storage. More efforts are still required to optimize the molecular designs of mRNA molecules with increased protein expression and enhanced structural stability. In addition, a variety of delivery systems are also needed to achieve effective delivery of vaccines. In this review, we highlight the advances in mRNA vaccines against various infectious diseases and discuss the molecular design principles and delivery systems of associated mRNA vaccines. The current state of the clinical application of mRNA vaccine pipelines against various infectious diseases and the challenge, safety, and protective effect of associated vaccines are also discussed.
Abstract The combined treatment of chemotherapeutant and microRNA (miR) has been proven to be a viable strategy for enhancing chemosensitivity due to its synergistic effect for tumor therapy. ...However, the co-delivery of drugs and genes remains a major challenge as they lack efficient co-delivery carriers. In this study, three amphiphilic star-branched copolymers comprising polylactic acid (PLA) and polydimethylaminoethyl methacrylate (PDMAEMA) with AB3 , (AB3 )2 ,and (AB3 )3 molecular architectures were synthesized respectively by a combination of ring-opening polymerization, atom transfer radical polymerization, and click chemistry via an “arm-first” approach. The star copolymers possessed a low critical micelle concentration (CMC) and formed nano-sized micelles with positive surface charges in water as well as exhibiting a much lower cytotoxicity than PEI 25 kDa. Nevertheless, their gene transfection efficiency and tumor inhibition ability showed a remarkable dependence on their molecular architecture. The (AB3 )3 architecture micelle copolymer exhibited the highest transfection efficiency, about 2.5 times higher than PEI. In addition, after co-delivering DOX and miR-21 inhibitor (miR-21i) into LN229 glioma cells, the micelles could mediate escaping miR-21i from lysosome degradation and the release of DOX to the nucleus, which significantly decreased the miR-21 expression. Moreover, co-delivery of DOX and miR-21i surprisingly exhibited an anti-proliferative efficiency compared with DOX or the miR-21i treatment alone. These results demonstrated that amphiphilic star-branched copolymers are highly promising for their combinatorial delivery of genes and hydrophobic therapeutants.
Glioblastoma (GBM) is the most aggressive type of brain tumor. Despite the multimodal therapies, the effectiveness of traditional treatments is not much satisfying. In recent years, immunotherapy has ...become the focus of tumor treatment. Unlike traditional treatments that directly target tumor cells, immunotherapy uses the body's immune system to kill tumors. However, due to the severe immunosuppressive microenvironment of GBM, it generally has a poor response to immunotherapy. In addition, the existence of the blood-brain barrier (BBB) also compromises the immunotherapeutic efficacy. Therefore, effective immunotherapy of GBM requires the therapeutic agents to not only efficiently cross the BBB but also relieve the strong immunosuppression of the tumor microenvironment of GBM. In this review, we will first introduce the CNS immune system, immunosuppressive mechanism of GBM, and current GBM immunotherapy strategies. Then, we will discuss the development of nanomaterials for GBM immunotherapy based on different strategies, roughly divided into four parts: immune checkpoint therapy, targeting tumor-associated immune cells, activating immune cells through immunogenic cell death, and combination therapy, to provide new insights for future GBM immunotherapy.
The long non-coding RNA Hox transcript antisense intergenic RNA (HOTAIR) was recently implicated in breast cancer metastasis and is predictive of poor prognosis in colorectal and pancreatic cancers. ...We recently discovered that HOTAIR is a cell cycle-related lncRNA in human glioma, and its expression is closely associated with glioma staging and poor prognosis. Although lysine specific demethylase 1 (LSD1) and polycomb repressive complex 2 (PRC2) have been demonstrated to be functional targets of HOTAIR, how HOTAIR regulates glioma cell cycle progression remains largely unknown. In this study, we found that EZH2 (predominant PRC2 complex component) inhibition blocked cell cycle progression in glioma cells, consistent with the effects elicited by HOTAIR siRNA. However, the inhibition of LSD1 did not affect cell cycle progression in glioma cells. These results suggest that HOTAIR might regulate cell cycle progression through EZH2. Our intracranial mice model also revealed delayed tumor growth in HOTAIR siRNA- and EZH2 inhibitor-treated groups. Moreover, in HOTAIR knock-down cell lines, the expression of the PRC2-binding domain of HOTAIR (5' domain) but not of the LSD1-binding domain of HOTAIR (3' domain) resulted in accelerated cell cycle progression. In conclusion, HOTAIR promotes cell cycle progression in glioma as a result of the binding of its 5' domain to the PRC2 complex.
Approximately 15-40% of all cancers develop metastases in the central nervous system (CNS), yet few therapeutic options exist to treat them. Cancer therapies based on monoclonal antibodies are widely ...successful, yet have limited efficacy against CNS metastases, owing to the low levels of the drug reaching the tumour site. Here, we show that the encapsulation of rituximab within a crosslinked zwitterionic polymer layer leads to the sustained release of rituximab as the crosslinkers are gradually hydrolysed, enhancing the CNS levels of the antibody by approximately tenfold with respect to the administration of naked rituximab. When the nanocapsules were functionalized with CXCL13-the ligand for the chemokine receptor CXCR5, which is frequently found on B-cell lymphoma-a single dose led to improved control of CXCR5-expressing metastases in a murine xenograft model of non-Hodgkin lymphoma, and eliminated lymphoma in a xenografted humanized bone marrow-liver-thymus mouse model. Encapsulation and molecular targeting of therapeutic antibodies could become an option for the treatment of cancers with CNS metastases.
Infection-related titanium implant failure rates remain exceedingly high in the clinic. Functional surface coating represents a very promising strategy to improve the antibacterial and bioactive ...properties of titanium alloy implants. Here, we describe a novel bioactive surface coating that consists of a mussel-inspired carboxymethyl chitosan hydrogel loaded with silver nanoparticles (AgNPs) to enhance the bioactive properties of the titanium alloy. The preparation of hydrogel is based on gallic acid grafted carboxymethyl chitosan (CMCS-GA) catalyzed by DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride). To build a firm bonding between the hydrogel and titanium alloy plate, a polydopamine layer was introduced onto the surface of the titanium alloy. With HRP/H2O2 catalysis, CMCS-GA can simply form a firm gel layer on the titanium alloy plate through the catechol groups. The surface properties of titanium alloy were characterized by scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS), and water contact angle. Silver nanoparticles were loaded into the gel layer by in situ reduction to enhance the antibacterial properties. In vitro antibacterial and cell viability experiments showed that the AgNPs-loaded Ti-gel possesses excellent antibacterial properties and did not affect the proliferation of rabbit mesenchymal stem cells (MSCs).
Innovations in nanotechnology have had an immense impact on medicine, such as in drug delivery, tissue engineering, and medical devices that combat different pathogens. The pathogens that may cause ...biofilm-associated nosocomial diseases are multidrug-resistant (MDR) bacteria, such as
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), including both Gram-positive and Gram-negative bacterial species. About 65-80% of infections are caused by biofilm-associated pathogens creating a move in the international community toward developing antimicrobial therapies to eliminate such pathogenic infections. Several nanomaterials (NMs) have been discovered and significantly employed in various antipathogenic therapies. These NMs have unique properties of singlet oxygen production, high absorption of near-infrared irradiation, and reasonable conversion of light to heat. In this review, functionalized NPs that combat different pathogenic infections are introduced. This review highlights NMs that combat infections caused by multidrug-resistant (MDR) and other pathogenic microorganisms. It also highlights the biomedical application of NPs with regard to antipathogenic activities.
Amplification of epidermal growth factor receptor (EGFR) and active mutant EGFRvIII occurs frequently in glioblastoma (GBM) and contributes to chemo/radio‐resistance in various cancers, especially in ...GBM. Elucidating the underlying molecular mechanism of temozolomide (TMZ) resistance in GBM could benefit cancer patients. A genome‐wide screening under a clustered regularly interspaced short palindromic repeats (CRISPR)‐Cas9 library is conducted to identify the genes that confer resistance to TMZ in EGFRvIII‐expressing GBM cells. Deep sgRNA sequencing reveals 191 candidate genes that are responsible for TMZ resistance in EGFRvIII‐expressing GBM cells. Notably, E2F6 is proven to drive a TMZ resistance, and E2F6 expression is controlled by the EGFRvIII/AKT/NF‐κB pathway. Furthermore, E2F6 is shown as a promising therapeutic target for TMZ resistance in orthotopic GBM cell line xenografts and GBM patient‐derived xenografts models. After integrating clinical data with paired primary–recurrent RNA sequencing data from 134 GBM patients who received TMZ treatment after surgery, it has been revealed that the E2F6 expression level is a predictive marker for TMZ response. Therefore, the inhibition of E2F6 is a promising strategy to conquer TMZ resistance in GBM.
A CRISPR‐Cas9 screening of temozolomide (TMZ) resistant glioblastoma cells is presented. NF‐κB is activated by TMZ treatment and EGFRvIII (epidermal growth factor receptor, EGFR) via PI3K/AKT, which leads to transcriptional induction of E2F6 expression. Cells with activated NF‐κB‐E2F6 survive under TMZ selection. TMZ withdrawal leads to cell proliferation and inhibition of NF‐κB/E2F6 prevents TMZ resistance.
Poor immunogenicity seriously hampers the broader implementation of antitumor immunotherapy. Enhanced immunogenicity capable of achieving greater antitumor immunity is urgently required. Here, a ...novel polymer that contains hydrophobic ferrocene (Fc) units and thioketal bonds in the main chain, which further delivered a prodrug of oxaliplatin and artesunate, i.e., Artoxplatin, to cancer cells is described. This polymer with Fc units in the nanoparticle can work as a polyigniter to spark the peroxide bonds in Artoxplatin and generate abundant reactive oxygen species (ROS) to kill cancers as nanobombig for cancer therapy. Moreover, ROS can trigger the breakdown of thioketal bonds in the polymer, resulting in the biodegradation of the polymer. Importantly, nanobombig can facilitate the maturation of dendritic cells and promote the activation of antitumor immunity, through the enhanced immunogenic cell death effect by ROS generated in situ. Furthermore, metabolomics analysis reveals a decrease in glutamine in nanobombig‐treated cancer cells, resulting in the upregulation of programmed death ligand 1 (PD‐L1). Consequently, it is further demonstrated enhanced tumor inhibitory effects when using nanobombig combined with anti‐PD‐L1 therapy. Overall, the nanosystem offers a rational design of an efficient chemo‐immunotherapy regimen to promote antitumor immunity by improving tumor immunogenicity, addressing the key challenges cancer immunotherapy faced.
A strategy for promoting chemo‐immunotherapy by simultaneously delivering oxaliplatin and artesunate into the tumor using a nanoparticle containing ferrocene units, named nanobombig, which facilitates the maturation of dendritic cells and promotes the activation of antitumor immune response, through the enhanced immunogenic cell death effect by reactive oxygen species generated in situ.
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