Optimized Fabrication of Dendritic Mesoporous Silica Nanoparticles as Efficient Delivery System for Cancer Immunotherapy.

In the past decade, cancer immunotherapy has revolutionized the field of oncology. Major immunotherapy approaches such as immune checkpoint inhibitors, cancer vaccines, adoptive cell therapy, cytokines, and immunomodulators have shown great promise in preclinical and clinical settings. Among them, immunomodulatory agents including cancer vaccines are particularly appealing; however, they face limitations, notably the absence of efficient and precise targeted delivery of immune-modulatory agents to specific immune cells and the potential for off-target toxicity. Nanomaterials can play a pivotal role in addressing targeting and other challenges in cancer immunotherapy. Dendritic mesoporous silica nanoparticles (DMSNs) can enhance the efficacy of cancer vaccines by enhancing the effective loading of immune modulatory agents owing to their tunable pore sizes. In this work, an emulsion-based method is optimized to customize the pore size of DMSNs and loaded DMSNs with ovalbumin (OVA) and cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (CpG-OVA-DMSNs). The immunotherapeutic effect of DMSNs is achieved through controlled chemical release of OVA and CpG in antigen-presenting cells (APCs). The results demonstrated that CpG-OVA-DMSNs efficiently activated the immune response in APCs and reduced tumor growth in the murine B16-OVA tumor model.

Multifunctional silica nanocomposites prime tumoricidal immunity for efficient cancer immunotherapy.

The tumor immune microenvironment (TIME) has been demonstrated to be the main cause of cancer immunotherapy failure in various malignant tumors, due to poor immunogenicity and existence of immunosuppressive factors. Thus, establishing effective treatments for hostile TIME remodeling has considerable potential to enhance immune response rates for durable tumor growth retardation. This study aims to develop a novel nanocomposite, polyethyleneimine-modified dendritic mesoporous silica nanoparticles loaded with microRNA-125a (DMSN-PEI@125a) to synergistically enhance immune response and immunosuppression reversion, ultimately generating a tumoricidal environment. Our results showed that DMSN-PEI@125a exhibited excellent ability in cellular uptake by murine macrophages and the cervical cancer cell line TC-1, repolarization of tumor associated macrophages (TAMs) to M1 type in a synergistic manner, and promotion of TC-1 immunogenic death. Intratumor injection of DMSN-PEI@125a facilitated the release of more damage-related molecular patterns and enhanced the infiltration of natural killer and CD8+ T cells. Meanwhile, repolarized TAMs could function as a helper to promote antitumor immunity, thus inhibiting tumor growth in TC-1 mouse models in a collaborative manner. Collectively, this work highlights the multifunctional roles of DMSN-PEI@125a in generating an inflammatory TIME and provoking antitumor immunity, which may serve as a potential agent for cancer immunotherapy.

Smart Protein-Based Formulation of Dendritic Mesoporous Silica Nanoparticles: Toward Oral Delivery of Insulin.

Oral insulin administration still represents a paramount quest that almost a century of continuous research attempts did not suffice to fulfill. Before pre-clinical development, oral insulin products have first to be optimized in terms of encapsulation efficiency, protection against proteolysis, and intestinal permeation ability. With the use of dendritic mesoporous silica nanoparticles (DMSNs) as an insulin host and together with a protein-based excipient, succinylated ß-lactoglobulin (BL), pH-responsive tablets permitted the shielding of insulin from early release/degradation in the stomach and mediated insulin permeation across the intestinal cellular membrane. Following an original in vitro cellular assay based on insulin starvation, direct cellular fluorescent visualization has evidenced how DMSNs could ensure the intestinal cellular transport of insulin.

Novel sensor array distinguishes heavy metal ions based on multiple fluorescence channels from dendritic mesoporous silica nanoparticles.

In this work, we demonstrated a sensor array with multiple fluorescence channels using dendritic mesoporous silica nanoparticles embedded with three quantum dots for the determination of four heavy metal ions (Hg2+, Cu2+, Cr3+, and Ag+). Carboxyl-modified CdTe QDs with three different fluorescence emission wavelengths were loaded onto a dendritic mesoporous supporter by an amidation reaction. The fluorescence sensor array exhibited excellent analytical performance for discrimination and semi-quantification of heavy metal ions from a single test, which simplified detection procedures. The four heavy metal ions exhibited different degrees of quenching of the fluorescence emission intensities of the three quantum dots and resulted in a variant data matrix for linear discriminant analysis. Under optimized conditions, the fluorescence sensor array discriminated the four heavy metal ions in a concentration range of 0.05-5 µmol/L, and semi-quantified Hg2+, Cu2+, Cr3+, and Ag+ with a limit of detection of 2.51 nmol/L, 5.15 nmol/L, 3.81 nmol/L, and 5.74 nmol/L, respectively. The fluorescence sensor array integrated the sensing units into a single nanoparticle instead of the complex multiple detection steps used in traditional sensor arrays, providing an alternative strategy for constructing a single-well sensing platform. Furthermore, the fluorescence sensor array showed great practical potential for distinguishing heavy metal ions in raw water and crayfish samples.

Delivery by Dendritic Mesoporous Silica Nanoparticles Enhances the Antimicrobial Activity of a Napsin-Derived Peptide Against Intracellular Mycobacterium tuberculosis.

Tuberculosis remains a serious global health problem causing 1.3 million deaths annually. The causative pathogen Mycobacterium tuberculosis (Mtb) has developed several mechanisms to evade the immune system and resistances to many conventional antibiotics, so that alternative treatment strategies are urgently needed. By isolation from bronchoalveolar lavage and peptide optimization, a new antimicrobial peptide named NapFab is discovered. While showing robust activity against extracellular Mtb, the activity of NapFab against intracellular bacteria is limited due to low intracellular availability. By loading NapFab onto dendritic mesoporous silica nanoparticles (DMSN) as a carrier system, cellular uptake, and consequently antimycobacterial activity against intracellular Mtb is significantly enhanced. Furthermore, using lattice light-sheet fluorescence microscopy, it can be shown that the peptide is gradually released from the DMSN inside living macrophages over time. By electron microscopy and tomography, it is demonstrated that peptide loaded DMSN are stored in vesicular structures in proximity to mycobacterial phagosomes inside the cells, but the nanoparticles are typically not in direct contact with the bacteria. Based on the combination of functional and live-cell imaging analyses, it is hypothesized that after being released from the DMSN NapFab is able to enter the bacterial phagosome and gain access to the bacilli.

Insights into the intraparticle morphology of dendritic mesoporous silica nanoparticles from electron tomographic reconstructions.

HYPOTHESIS: Although many synthetic pathways allow to fine-tune the morphology of dendritic mesoporous silica nanoparticles (DMSNs), the control of their particle size and mesopore diameter remains a challenge. Our study focuses on either increasing the mean particle size or adjusting the pore size distribution, changing only one parameter (particle or pore size) at a time. The dependence of key morphological features (porosity; pore shape and pore dimensions) on radial distance from the particle center has been investigated in detail. EXPERIMENTS: Three-dimensional reconstructions of the particles obtained by scanning transmission electron microscopy (STEM) tomography were adapted as geometrical models for the quantification of intraparticle morphologies by radial porosity and chord length distribution analyses. Structural properties of the different synthesized DMSNs have been complementary characterized using TEM, SEM, nitrogen physisorption, and dynamic light scattering. FINDINGS: The successful independent tuning of particle and pore sizes of the DMSNs could be confirmed by conventional analysis methods. Unique morphological features, which influence the uptake and release of guest molecules in biomedical applications, were uncovered from analyzing the STEM tomography-based reconstructions. It includes the quantification of structural hierarchy, identification of intrawall openings and pores, as well as the distinction of pore shapes (conical vs. cylindrical).

In Vivo Sustained Release of Peptide Vaccine Mediated by Dendritic Mesoporous Silica Nanocarriers.

Mesoporous silica nanoparticles have drawn increasing attention as promising candidates in vaccine delivery. Previous studies evaluating silica-based vaccine delivery systems concentrated largely on macromolecular antigens, such as inactivated whole viruses. In this study, we synthesized dendritic mesoporous silica nanoparticles (DMSNs), and we evaluated their effectiveness as delivery platforms for peptide-based subunit vaccines. We encapsulated and tested in vivo an earlier reported foot-and-mouth disease virus (FMDV) peptide vaccine (B2T). The B2T@DMSNs formulation contained the peptide vaccine and the DMSNs without further need of other compounds neither adjuvants nor emulsions. We measured in vitro a sustained release up to 930 h. B2T@DMSNs-57 and B2T@DMSNs-156 released 23.7% (135 µg) and 22.8% (132 µg) of the total B2T. The formation of a corona of serum proteins around the DMSNs increased the B2T release up to 61% (348 µg/mg) and 80% (464 µg/mg) for B2T@DMSNs-57 and B2T@DMSNs-156. In vitro results point out to a longer sustained release, assisted by the formation of a protein corona around DMSNs, compared to the reference formulation (i.e., B2T emulsified in Montanide). We further confirmed in vivo immunogenicity of B2T@DMSNs in a particle size-dependent manner. Since B2T@DMSNs elicited specific immune responses in mice with high IgG production like the reference B2T@Montanide™, self-adjuvant properties of the DMSNs could be ascribed. Our results display DMSNs as efficacious nanocarriers for peptide-based vaccine administration.

Emission Wavelength Switchable Carbon Dots Combined with Biomimetic Inorganic Nanozymes for a Two-Photon Fluorescence Immunoassay.

In this work, o-phenylenediamine is utilized as a precursor to synthesize the fluorescent emission wavelength switchable carbon dots (o-CDs). Our investigation reveals that ferrous ions (Fe2+) can effectively induce fluorescence quenching of o-CDs by chelation and aggregation. After the addition of hydrogen peroxide (H2O2), the fluorescence of o-CDs recovers and the fluorescent color changes from yellow to green. As far as we know, o-CDs are the first reported CDs with switchable fluorescence emission wavelength. In order to fabricate an enzyme-free immunosensor, an amino-functionalized dendritic mesoporous silica nanoparticle (DMSN)-gold nanoparticle (Au NP) nanostructure was fabricated as a glucose oxidase mimetic nanoenzyme by in situ coating of the Au NPs on the surface of the DMSNs. Then, the functionalized DMSN-Au NPs were modified on the detection antibody and hydrolyzed with glucose to produce H2O2. This immune induced recognition strategy combines with the o-CDs+Fe2+ signal generation system to achieve specific and sensitive detection of the target. The replacement of glucose oxidase by DMSN-Au NPs not only reduces the cost but also provides significantly amplified signals due to DMSNs haing a high specific surface area. We show the detection of carcinoembryonic antigen (CEA) as an example target to evaluate the analytical figure of merits of the proposed strategy. Under the optimal conditions, two-photon-based o-CDs displayed excellent performances for CEA and the limit of detection as low as 74.5 pg/mL with a linear range from 0.1 to 80 ng/mL. The proposed fluorescent immunosensor provides an optional and potential scheme for low cost, high sensitivity, and versatile discovery of clinical biomarkers.

Targeted Therapeutic-Immunomodulatory Nanoplatform Based on Noncrystalline Selenium.

Developing versatile nanomaterials has offered a myriad of opportunities to surmount cancer. In particular, the combination of therapy and immunomodulatory effect to further enhance immune response provides a new idea for effective tumor treatment. Herein, for the first time, an in situ growth strategy is developed to construct highly dispersed noncrystalline selenium nanoparticles (Se NPs) with thiolated cyclo(Arg-Gly-Asp-Phe-Lys-(mpa)) (RGD) peptide modification (R-Se@DMSND) for targeted cancer treatment. Se NPs could be homogeneously grown into the pore channels of dendritic mesoporous silica nanoparticles (DMSNs) since the DMSNs could stabilize Se NPs to prevent their aggregations. Moreover, Se NPs could not only act as a therapeutic agent, inducing ROS overproduction, to effectively suppress primary tumor but also as an immunomodulatory agent to simultaneously inhibit the growth of secondary tumors by enhancement of the immune response, as confirmed by the in vivo results. Such the therapeutic-immunomodulatory strategy for tumorous therapy combining with immunomodulation using one simple nanoplatform may pave a new avenue in the biomedical field.

Rational Design of Multifunctional Dendritic Mesoporous Silica Nanoparticles to Load Curcumin and Enhance Efficacy for Breast Cancer Therapy.

Breast cancer is the primary reason for cancer-related death in women worldwide and the development of new formulations to treat breast cancer patients is crucial. Curcumin (Cur), a natural product, exerts promising anticancer activities against various cancer types. However, its therapeutic efficacy is hindered as a result of poor water solubility, instability, and low bioavailability. The aim of this work is to assess the curative effect of a novel nanoformulation, i.e., Cur-loaded and calcium-doped dendritic mesoporous silica nanoparticles modified with folic acid (Cur-Ca@DMSNs-FA) for breast cancer therapy. The results manifested that Cur-Ca@DMSNs-FA dispersed very well in aqueous solution, released Cur with a pH-responsible profile, and targeted efficiently to human breast cancer MCF-7 cells. Further investigations indicated that Cur-Ca@DMSNs-FA effectively inhibited cell proliferation, increased intracellular ROS generation, decreased mitochondrial membrane potential, and enhanced cell cycle retardation at G2/M phase, leading to a higher apoptosis rate in MCF-7 compared to free Cur. Moreover, the Western blotting analysis demonstrated that Cur-Ca@DMSNs-FA were more active than free Cur through suppression of PI3K/AKT/mTOR and Wnt/ß-catenin signaling, and activation of the mitochondria-mediated apoptosis pathway. In addition, hemolysis assay showed that the Ca@DMSNs-FA exhibited good biocompatibility. Last, in vivo studies indicated that when Cur was encapsulated in Ca@DMSNs-FA, the Cur concentration in blood serum and tumor tissues was increased after 1 h intraperitoneal injection. In conclusion, Cur-Ca@DMSNs-FA might act as a potential anticancer drug formulation for breast cancer therapy.