An ultrasensitive electrochemiluminescence immunosensor for SARS-CoV-2 nucleocapsid protein detection based on signal amplification strategy of DMSN@QDs

Based on signal amplification strategy of dendritic mesoporous silica nanospheres loaded with CdSe/ZnS quantum dots (DMSN@QDs), an ultrasensitive electrochemiluminescence (ECL) immunosensor with magnetic separation was constructed for the detection of SARS-CoV-2 nucleocapsid protein (NP). DMSN, a mesoporous material with abundant radial pores, large specific surface area and high porosity, can increase the loading capacity of QDs and hinder their aggregation as the nanocarrier. DMSN@QDs with good ECL efficiency were used as signal labels to construct a sandwich immunosensor. The designed ECL immunosensor displayed a good linear relationship for NP concentrations ranging from 0.005 ng mL(-1) to 50 ng mL(-1), with a limit of detection of 3.33 pg mL(-1). The ECL immunosensor was successfully applied to detect NP in human serum samples with satisfactory recovery. This strategy provided a new method for detecting NP and expanded the application field of DMSN.

Medicinal bismuth: Bismuth-organic frameworks as pharmaceutically privileged compounds

Historically organometallic compounds have been used to cure certain diseases with limited applications. Although bismuth belongs to the category of heavy metals, many of its derivatives have found applications in modern drug discovery research, mainly because of its low toxicity and higher bioavailability. Being an eco-friendly mild Lewis acid, compounds having bismuth as a central atom are capable of binding several proteins in humans and other species. Bismuth complexes demonstrated antibacterial potential in syphilis, diarrhea, gastritis, and colitis. Apart from antibacterial activities, bismuth compounds exhibited anticancer, antileishmanial, and some extent of antifungal and other medicinal properties. This article discusses major synthetic methods and pharmacological potentials of bismuth complexes exhibiting in vitro activity to significant clinical performance in a systematic and timely manner.Copyright © 2022 Elsevier Ltd

STING agonist-loaded mesoporous manganese-silica nanoparticles for vaccine applications.

Cyclic dinucleotides (CDNs), as one type of Stimulator of Interferon Genes (STING) pathway agonist, have shown promising results for eliciting immune responses against cancer and viral infection. However, the suboptimal drug-like properties of conventional CDNs, including their short in vivo half-life and poor cellular permeability, compromise their therapeutic efficacy. In this study, we have developed a manganese-silica nanoplatform (MnOx@HMSN) that enhances the adjuvant effects of CDN by achieving synergy with Mn2+ for vaccination against cancer and SARS-CoV-2. MnOx@HMSN with large mesopores were efficiently co-loaded with CDN and peptide/protein antigens. MnOx@HMSN(CDA) amplified the activation of the STING pathway and enhanced the production of type-I interferons and other proinflammatory cytokines from dendritic cells. MnOx@HMSN(CDA) carrying cancer neoantigens elicited robust antitumor T-cell immunity with therapeutic efficacy in two different murine tumor models. Furthermore, MnOx@HMSN(CDA) loaded with SARS-CoV-2 antigen achieved strong and durable (up to one year) humoral immune responses with neutralizing capability. These results demonstrate that MnOx@HMSN(CDA) is a versatile nanoplatform for vaccine applications.

Virus Inactivation Based on Optimal Surfactant Reservoir of Mesoporous Silica.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) caused a pandemic in 2019 and reaffirmed the importance of environmental sanitation. To prevent the spread of viral infections, we propose the application of a mesoporous silica (MS)-based virus-inactivating material. MS is typically synthesized using a micellar surfactant template; hence, the intermediate before removal of the surfactant template is expected to have a virus-inactivating activity. MS-CTAC particles filled with cetyltrimethylammonium chloride (CTAC), a cationic surfactant with an alkyl chain length of 16, were used to test this hypothesis. Plaque assays revealed that the MS-CTAC particles inactivated the enveloped bacteriophage φ6 by approximately 4 orders of magnitude after a contact time of 10 min. The particles also indicated a similar inactivation effect on the nonenveloped bacteriophage Qß. In aqueous solution, CTAC loaded on MS-CTAC was released until the equilibrium concentration of loading and release on MS was reached. The released CTAC acted on viruses. Thus, MS is likely a good reservoir for the micellar surfactant. Surfactant readsorption also occurred in the MS particles, and the highest retention rate was observed when micellar surfactants with alkyl chain lengths appropriate for the pore size were used. The paper containing MS-CTAC particles was shown to maintain stable viral inactivation for at least three months in a typical indoor environment. Applying this concept to indoor wallpaper and air-conditioning filters could contribute to the inactivation of viruses in aerosols. These findings open possibilities for mesoporous materials with high surface areas, which can further develop into virus inactivation materials.

Aptamer-Gated Mesoporous Silica Nanoparticles for N Protein Triggered Release of Remdesivir and Treatment of Novel Coronavirus (2019-nCoV).

Since the 2019-nCoV outbreak was first reported, hundreds of millions of people all over the world have been infected. There is no doubt that improving the cure rate of 2019-nCoV is one of the most effective means to deal with the current serious epidemic. At present, Remdesivir (RDV) has been clinically proven to be effective in the treatment of SARS-CoV-2. However, the uncertain side effects make it important to reduce the use of drugs while ensuring the self-healing effect. We report an approach here with targeted therapy for the treatment of SARS-CoV-2 and other coronaviruses illness. In this study, mesoporous silica was used as the carrier of RDV, the nucleocapsid protein (N protein) aptamer was hybridized with the complementary chain, and the double-stranded DNA was combined with gold nanoparticles as the gates of mesoporous silica pores. When the RDV-loaded mesoporous silica is incubated with the N protein, aptamer with gold nanoparticles dissociate from the complementary DNA oligonucleotide on the mesoporous silica surface and bind to the N protein. The releasing of RDV was determined by detecting the UV-vis absorption peak of RDV in the solution. These results show that the RDV delivery system designed in this work has potential clinical application for the treatment of 2019-nCoV.

Highly sensitive aptasensor for the detection of SARS-CoV-2-RBD using aptamer-gated methylene blue@mesoporous silica film/laser engraved graphene electrode.

Herein, an aptasensor was designed to detect the receptor-binding domain of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2-RBD) based on the encapsulation of the methylene blue (MB) inside the mesoporous silica film (MPSF), and an aptamer as an electrochemical probe, a porous matrix, and a bio-gatekeeper, respectively. The signal analysis of the proposed aptasensor indicated that the surface coverage of the encapsulated MB inside the MPSF (MB@MPSF) was 1.9 nmol/cm2. Aptamers were capped the MB@MPSF, avoiding the release of MB into the solution via the electrostatic attraction between the positively charged amino groups of the MPSF and negatively charged phosphate groups of the aptamers. Therefore, the electrochemical signal of the encapsulated MB in the absence of the SARS-CoV-2-RBD was high. In the presence of SARS-CoV-2-RBD, the aptamers that had a high affinity to the SARS-CoV-2-RBD molecules were removed from the electrode surface to interact with SARS-CoV-2-RBD. It gave rise to the release of the MB from the MPSF to the solution and washed away on the electrode surface. Therefore, the electrochemical signal of the aptasensor decreased. The electrochemical signal was recorded with a square wave voltammetry technical in the range of 0.5-250 ng/mL of SARS-CoV-2-RBD in a saliva sample. The limit of detection was found to be 0.36 ng/mL. Furthermore, the selectivity factor values of the proposed aptasensor to 32 ng/mL SARS-CoV-2-RBD in the presence of C-reactive protein, hemagglutinin, and neuraminidase of influenza A virus were 35.9, 11.7, and 17.37, respectively, indicating the high selectivity of the proposed aptasensor.

Detection of viruses by probe-gated silica nanoparticles directly from swab samples.

Viral infection has been one of the major health issues for human life. The real-time reverse transcription polymerase chain reaction (RT-PCR)-based detection has primarily been used for virus detection as a highly reliable procedure. However, it is a relatively long and multi-stage process. In addition, required skilled personnel and complex instrumentation presents difficulties in large scale monitoring efforts. Therefore, we report here a direct and fast detection method for CoV-2 genome as applied in the nose-throat swab samples without any further processing. The detection principle is based on fluorescein-loaded mesoporous silica nanoparticles capped by specific gene sequences probes immobilized on the surface of the nanoparticles. Upon hybridization with the target viral genome, the fluorescein molecules were released from the mesopores. Testing with synthetic oligonucleotides, the NSP12 gene-based detection resulted in a strong signal. Target detection time could be optimized to 15 min and the limit of detection was 1.4 RFU with 84% sensitivity with clinical samples (n = 43).

Recent Advances in the Use of Mesoporous Silica Nanoparticles for the Diagnosis of Bacterial Infections.

Public awareness of infectious diseases has increased in recent months, not only due to the current COVID-19 outbreak but also because of antimicrobial resistance (AMR) being declared a top-10 global health threat by the World Health Organization (WHO) in 2019. These global issues have spiked the realization that new and more efficient methods and approaches are urgently required to efficiently combat and overcome the failures in the diagnosis and therapy of infectious disease. This holds true not only for current diseases, but we should also have enough readiness to fight the unforeseen diseases so as to avoid future pandemics. A paradigm shift is needed, not only in infection treatment, but also diagnostic practices, to overcome the potential failures associated with early diagnosis stages, leading to unnecessary and inefficient treatments, while simultaneously promoting AMR. With the development of nanotechnology, nanomaterials fabricated as multifunctional nano-platforms for antibacterial therapeutics, diagnostics, or both (known as "theranostics") have attracted increasing attention. In the research field of nanomedicine, mesoporous silica nanoparticles (MSN) with a tailored structure, large surface area, high loading capacity, abundant chemical versatility, and acceptable biocompatibility, have shown great potential to integrate the desired functions for diagnosis of bacterial infections. The focus of this review is to present the advances in mesoporous materials in the form of nanoparticles (NPs) or composites that can easily and flexibly accommodate dual or multifunctional capabilities of separation, identification and tracking performed during the diagnosis of infectious diseases together with the inspiring NP designs in diagnosis of bacterial infections.

A Modular Biomaterial Scaffold-Based Vaccine Elicits Durable Adaptive Immunity to Subunit SARS-CoV-2 Antigens.

The coronavirus disease 2019 (COVID-19) pandemic demonstrates the importance of generating safe and efficacious vaccines that can be rapidly deployed against emerging pathogens. Subunit vaccines are considered among the safest, but proteins used in these typically lack strong immunogenicity, leading to poor immune responses. Here, a biomaterial COVID-19 vaccine based on a mesoporous silica rods (MSRs) platform is described. MSRs loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF), the toll-like receptor 4 (TLR-4) agonist monophosphoryl lipid A (MPLA), and SARS-CoV-2 viral protein antigens slowly release their cargo and form subcutaneous scaffolds that locally recruit and activate antigen-presenting cells (APCs) for the generation of adaptive immunity. MSR-based vaccines generate robust and durable cellular and humoral responses against SARS-CoV-2 antigens, including the poorly immunogenic receptor binding domain (RBD) of the spike (S) protein. Persistent antibodies over the course of 8 months are found in all vaccine configurations tested and robust in vitro viral neutralization is observed both in a prime-boost and a single-dose regimen. These vaccines can be fully formulated ahead of time or stored lyophilized and reconstituted with an antigen mixture moments before injection, which can facilitate its rapid deployment against emerging SARS-CoV-2 variants or new pathogens. Together, the data show a promising COVID-19 vaccine candidate and a generally adaptable vaccine platform against infectious pathogens.

Targeted-lung delivery of dexamethasone using gated mesoporous silica nanoparticles. A new therapeutic approach for acute lung injury treatment.

Acute lung injury (ALI) is a critical inflammatory syndrome, characterized by increased diffuse inflammation and severe lung damage, which represents a clinical concern due to the high morbidity and mortality in critical patients. In last years, there has been a need to develop more effective treatments for ALI, and targeted drug delivery to inflamed lungs has become an attractive research field. Here, we present a nanodevice based on mesoporous silica nanoparticles loaded with dexamethasone (a glucocorticoid extensively used for ALI treatment) and capped with a peptide that targets the TNFR1 receptor expressed in pro-inflammatory macrophages (TNFR-Dex-MSNs) and avoids cargo leakage. TNFR-Dex-MSNs nanoparticles are preferentially internalized by pro-inflammatory macrophages, which overexpressed the TNFR1 receptor, with the subsequent cargo release upon the enzymatic hydrolysis of the capping peptide in lysosomes. Moreover, TNFR-Dex-MSNs are able to reduce the levels of TNF-α and IL-1ß cytokines in activated pro-inflammatory M1 macrophages. The anti-inflammatory effect of TNFR-Dex-MSNs is also tested in an in vivo ALI mice model. The administered nanodevice (intravenously by tail vein injection) accumulated in the injured lungs and the controlled dexamethasone release reduces markedly the inflammatory response (TNF-α IL-6 and IL-1ß levels). The attenuation in lung damage, after treatment with TNFR-Dex-MSNs, is also confirmed by histopathological studies. Besides, the targeted-lung dexamethasone delivery results in a decrease of dexamethasone derived side-effects, suggesting that targeted nanoparticles can be used for therapy in ALI and could help to overcome the clinical limitations of current treatments.