Search

Ferrofluids have been extensively employed in industrial, environmental, and biomedical areas. Among them, fluorous ferrofluids are of particular interest because of the biorthogonal nature of perfluorocarbons (PFCs). However, the noninteracting nature of PFCs as well as challenges in functionalization of nanoparticle surfaces with fluorous ligands has limited their applications, especially in biomedicine. In particular, commercially available fluorous ferrofluids are stabilized using ionic surfactants with charged groups that physically interact with a wide range of charged biological molecules. In this paper, we developed a unique two-phase ligand attachment strategy to render stable fluorous ferrofluids using nonionic surfactants. The superparamagnetic Fe 3 O 4 or MnFe 2 O 4 core of the magnetic nanoparticles, the magnetic component of the ferrofluid, was coated with a silica shell containing abundant surface hydroxyl groups, thereby enabling the installation of fluorous ligands through stable covalent, neutral, siloxane bonds. We explored chemistry-material relationships between different ligands and PFC solvents and found that low-molecular-weight ligands can assist with the installation of high-molecular-weight ligands (4000-8000 g/mol), allowing us to systematically control the size and thickness of ligand functionalization on the nanoparticle surface. By zero-field-cooled magnetization measurements, we studied how the ligands affect magnetic dipole orientation forces and observed a curve flattening that is only associated with the ferrofluids. This work provided insight into ferrofluids' dependence on interparticle interactions and contributed a methodology to synthesize fluorous ferrofluids with nonionic surfactants that exhibit both magnetic and chemical stability. We believe that the doped MnFe 2 O 4 fluorous ferrofluid has the highest combination of stability and magnetization reported to date., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Vaccination is the most important way of population protection from life-threatening pathogenic infections. However, its efficiency is frequently compromised by a failure of strong antigen presentation and immune activation. Herein, we developed virus-like magnetic mesoporous silica nanoparticles as a universal vaccination platform (termed MagParV) for preventing pathogenic infections. This platform was constructed by integrating synthetic biology-based endoplasmic reticulum-targeting vesicles with magnetic mesoporous silica particles. This platform exhibited high antigen-loading capacity, strongly targeting the endoplasmic reticulum and promoting antigen presentation in dendritic cells. After prime-boost vaccination, the antigen-loading MagParV with AMF drastically elicited specific antibody production against corresponding antigens of fungal, bacterial, and viral pathogens. A systemic infection model further revealed that the platform effectively protected the mice from severe fungal systemic infections. This study realized synthetic biology-facilitated green manufacturing of vaccines, which is promising for magnetism-activated vaccination against different kinds of pathogenic infections.

Unicellular bacterial cells exhibit diverse population behaviors (i.e., aggregation, dispersion, directed assembly, biofilm formation, etc.) to facilitate communication and cooperation. Suitable bacterial behaviors are required for efficient nutrient uptake, cell recycling, and stress response for environmental and industrial application of bacterial populations. However, it remains a great challenge to artificially control bacterial behaviors because of complicated genetic and biochemical mechanisms. In this study, we designed facile mesoporous silica nanoparticle (MSN)-based assemblies to intelligently regulate bacterial behaviors with the help of light and magnetic field. This system was composed of magnetic MSNs, i.e., MnFe 2 O 4 @CoFe 2 O 4 @MSN modified by photoactive spiropyran (SP), and the chitosan-based polymers ChiPSP, i.e., chitosan grafted by triphenylphosphine and SP. The assembly strongly bound bacterial cells, inducing reversible bacterial aggregation by visible-light irradiation and dark. Moreover, the formed bacterial aggregates could be further governed by a directed magnetic field (DMF) to form microfibers and by an alternating magnetic field (AMF) to form biofilms. This study realized stimulus-triggered regulation of bacterial behaviors by MSNs and implied the great power of chemical strategies in intelligent control of diverse biological processes for environmental and industrial applications.

Magnetic resonance imaging (MRI)-guided high-intensity focused ultrasound (HIFU) has been applied as a therapeutic tool in the clinic, and enhanced MRI contrast for depiction of target tissues will improve the precision and applicability of HIFU therapy. This work presents a "spotlight MRI" contrast enhancement technique, which combines four essential components: periodic HIFU stimulation, strong modulation of T 1 caused by HIFU, rapid MRI signal collection, and spotlight MRI spectral signal processing. The T 1 modulation is enabled by a HIFU-responsive nanomaterial based on mesoporous silica nanoparticles with Pluronic polymers (Poloxamers) and MRI contrast agents attached. With periodic HIFU stimulation in a precisely defined region containing the nanomaterial, strong periodic MRI T 1 -weighted signal changes are generated. Rapid MRI signal collection of the periodic signal changes is realized by a rapid dynamic 3D MRI technique, and spotlight MRI spectral signal processing creates modulation enhancement maps (MEM) that suppress background signal and spotlight the spatial location with nanomaterials experiencing HIFU stimulation. In particular, a framework is presented to analyze the trade-offs between different parameter choices for the signal processing method. The optimal parameter choices under a specific experimental setting achieved MRI contrast enhancement of more than 2 orders of magnitude at the HIFU focal point, compared to controls.

Stimuli-responsive multifunctional mesoporous silica nanoparticles (MSNs) have been studied intensively during the past decade. A large variety of mesopore capping systems have been designed, initially to show that it could be done and later for biomedical applications such as drug delivery and imaging. On-command release of cargo molecules such as drugs from the pores can be activated by a variety of stimuli. This paper focuses on three noninvasive, biologically usable external stimuli: magnetism, ultrasound, and light. We survey the variety of MSNs that have been and are being used and assess capping designs and the advantages and drawbacks of the nanoplatforms' responses to the various stimuli. We discuss important recent advances, their basic mechanisms, and their requirements for stimulation. On the basis of our survey, we identify fundamental challenges and suggest future directions for research that will unleash the full potential of these fascinating nanosystems for clinical applications.

Physically stimulated nanoparticles that deliver size-selected cargo and function as logic gates are reported. To achieve this goal the particle requires multiple components, and we recognized early on that the components, not just the released cargo, could be used to demonstrate logic operations (OR and AND logic). For stimuli, we chose two non-invasive types, red light and alternating magnetic fields (AMF), because they both have potential biological relevance. To realize cargo delivery with size selection and logic operations, we mechanized the surface of core@shell nanoparticles with a superparamagnetic core that generates localized heating when exposed to an AMF, and a mesoporous silica shell into which cargo molecules with different sizes were loaded. We demonstrate the core@shell nanoparticles can load the dual cargos with different sizes and subsequently release the smaller (∼0.5 nm) and bigger (∼2 nm) cargos in succession when stimulated by a red light followed by an AMF. Finally, we demonstrate that the multi-component nanoparticles could function as nanoparticle-based Boolean logic gates where AMF and red light served as the two inputs and the release of small cargo, and free cyclodextrin served as the outputs. The construction of two Boolean logic gates (OR, and AND) was realized.

We developed a theranostic approach exemplifying a concept called an "exchange method" that controls and "images" drug release from nanoparticles using magnetic resonance imaging-guided high-intensity focused ultrasound. The controllable amount of released drug and therapeutic efficacy can be self-reported by associated MRI contrast changes in solution and in cells.

Pathogenic biofilms protected by extracellular polymeric substances frequently compromise the efficiency of antibacterial drugs and severely threaten human health. In this study, we designed a multi-stimuli-responsive magnetic supramolecular nanoplatform to co-deliver large and low molecular weight drugs for synergistic eradication of pathogenic biofilms. This co-delivery platform was composed of mesoporous silica nanoparticles (MSNs) with large pores (MSNLP) capped by β-cyclodextrin (β-CD)-modified polyethylenimine (PEICD) and adamantane (ADA)-decorated MSNs containing a magnetic core (MagNP@MSNA) capped by cucurbit[6]uril (CB[6]). The host MSNs ( H , MSNLP@PEICD) and the guest MSNs ( G , MagNP@MSNA-CB[6]) spontaneously form coassemblies ( H+G ), based on the host-guest interactions between β-CD and ADA. Under the stimulus of pathogen cells together with heating by an alternating magnetic field (AMF), the supramolecular coassemblies released both the large molecular weight antimicrobial peptide melittin (MEL) and the low molecular weight antibiotic ofloxacin (OFL) with high efficiency. As compared to free drugs (MEL and OFL) or unattached MSNs ( H or G ), the drug-loading H+G coassemblies ( H -MEL+ G -OFL) exhibited much higher capacity for biofilm eradication, thoroughly removing biofilm biomass and killing the pathogenic cells, and displaying no obvious toxicity to mammalian cells. This strong antibiofilm capacity was severely decreased when the host and guest components were prevented from coassembling but administered simultaneously, revealing the critical role of the supramolecular assembly in biofilm removal. Moreover, an in vivo implantation model showed that the coassemblies eradicated the pathogenic biofilms from the implants, preventing host tissue damage and inflammation. Therefore, the co-delivering and multi-stimuli-responsive nanocarriers could overcome the anti-infection difficulties during treatment of infections because of protective biofilms.

In the presence of an alternating magnetic field (AMF), a superparamagnetic iron oxide nanoparticle (SPION) generates heat. Understanding the local heating mechanism of a SPION in suspension and in a mesoporous silica nanoparticle (MSN) will advance the design of hyperthermia-based nanotheranostics and AMF-stimulated drug delivery in biomedical applications. The AMF-induced heating of single-domain SPION can be explained by the Néel relaxation (reorientation of the magnetization) or the Brownian relaxation (motion of the particle). The latter is investigated using fluorescence depolarization based on detecting the mobility-dependent polarization anisotropy ( r ) of two luminescence emission bands at different wavelengths corresponded to the europium-doped luminescent SPION (EuSPION) core and the silica-based intrinsically emitting shell of the core-shell MSN. The fluorescence depolarization experiments are carried out with both the free and the silica-encapsulated SPION nanoparticles with and without application of the AMF. The r value of a EuSPION core-mesoporous silica shell in the presence of the AMF does not change, indicating that no additional rotational motion of the core-shell nanoparticles is induced by the AMF, disproving the contribution of Brownian heating and thus supporting Néel relaxation as the dominant heating mechanism.

A potent class of isoquinoline-based α-N-heterocyclic carboxaldehyde thiosemicarbazone (HCT) compounds has been rediscovered; based upon this scaffold, three series of antiproliferative agents were synthesized through iterative rounds of methylation and fluorination modifications, with anticancer activities being potentiated by physiologically relevant levels of copper. The lead compound, HCT-13 , was highly potent against a panel of pancreatic, small cell lung carcinoma, prostate cancer, and leukemia models, with IC 50 values in the low-to-mid nanomolar range. Density functional theory (DFT) calculations showed that fluorination at the 6-position of HCT-13 was beneficial for ligand-copper complex formation, stability, and ease of metal-center reduction. Through a chemical genomics screen, we identify DNA damage response/replication stress response (DDR/RSR) pathways, specifically those mediated by ataxia-telangiectasia and Rad3-related protein kinase (ATR), as potential compensatory mechanism(s) of action following HCT-13 treatment. We further show that the cytotoxicity of HCT-13 is copper-dependent, that it promotes mitochondrial electron transport chain (mtETC) dysfunction, induces production of reactive oxygen species (ROS), and selectively depletes guanosine nucleotide pools. Lastly, we identify metabolic hallmarks for therapeutic target stratification and demonstrate the in vivo efficacy of HCT-13 against aggressive models of acute leukemias in mice., (This journal is © The Royal Society of Chemistry 2020.)

A novel self-assembling peptide-functionalized core-shell mesoporous silica nanoparticle was developed as a drug carrier. Superparamagnetic manganese- and cobalt-doped iron oxide nanoparticles formed the core for the mesoporous silica shell coating. On the silica outer shell, the peptide Boc-Phe-Phe-Gly-Gly-COOH was covalently conjugated by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N -hydroxysulfosuccinimide sodium salt coupling. The self-assembling property of the peptide at physiological temperature was utilized to block the pore openings, while the disassembly at elevated local particle temperature released cargo molecules without bulk heating that would cause cell damage. Both conventional heating and heating in an alternating magnetic field were tested for the release of fluorescein and daunorubicin. In vitro experiments showed high cytotoxicity on pancreatic carcinoma cells (PANC-1) when this delivery system was activated by an alternating magnetic field, while control particles without drugs showed no obvious cytotoxicity.

Magnetic resonance imaging (MRI) is an essential modality for clinical diagnosis, and MRI-guided high-intensity focused ultrasound (MRgHIFU) is a powerful technology for targeted therapy. Clinical applications of MRgHIFU primarily utilize hyperthermia and ablation to treat cancerous tissue, but for drug delivery applications thermal damage is undesirable. A biofriendly MRgHIFU-responsive mesoporous silica nanoparticle (MSN) platform that is stimulated within a physiological safe temperature range has been developed, reducing the possibility of thermal damage to the surrounding healthy tissues. Biocompatible polyethylene glycol (PEG) was employed to cap the pores of MSNs, and the release of cargo molecules by HIFU occurs without substantial temperature increase (∼4 °C). To visualize by MRI and measure the stimulated delivery in situ, a U.S. Food and Drug Administration (FDA)-approved gadolinium-based contrast agent, gadopentetate dimeglumine (Gd(DTPA) 2- ), was used as the imageable cargo. Taking advantage of the three-dimensional (3-D) imaging and targeting capabilities of MRgHIFU, the release of Gd(DTPA) 2- stimulated by HIFU was pinpointed at the HIFU focal point in 3-D space in a tissue-mimicking gel phantom. The amount of Gd(DTPA) 2- released was controlled by HIFU stimulation times and power levels. A positive correlation between the amount of Gd(DTPA) 2- released and T 1 was found. The MRgHIFU-stimulated cargo release was further imaged in a sample of ex vivo animal tissue. With this technology, the biodistribution of the nanocarriers can be tracked and the MRgHIFU-stimulated cargo release can be pinpointed, opening up an opportunity for future image-guided theranostic applications.

Periodic high-intensity focused ultrasound modulation of a nanoparticle generates reversible MRI T1 relaxivity changes at the 1.5 mm3 focal point causing periodic T1-weighted signal changes. Fourier analysis extracts signal changes at the modulation frequency, and a modulation enhancement map spotlights the precise region of interest by increasing contrast almost 100-fold.

Tissue is translucent to shortwave infrared (SWIR) light, rendering optical imaging superior in this region. However, the widespread use of optical SWIR imaging has been limited, in part, by the lack of bright, biocompatible contrast agents that absorb and emit light above 1000 nm. J-Aggregation offers a means to transform stable, near-infrared (NIR) fluorophores into red-shifted SWIR contrast agents. Here we demonstrate that J-aggregates of NIR fluorophore IR-140 can be prepared inside hollow mesoporous silica nanoparticles (HMSNs) to result in nanomaterials that absorb and emit SWIR light. The J-aggregates inside PEGylated HMSNs are stable for multiple weeks in buffer and enable high resolution imaging in vivo with 980 nm excitation.

Triapine (3-AP), is an iron-binding ligand and anticancer drug that is an inhibitor of human ribonucleotide reductase (RNR). Inhibition of RNR by 3-AP results in the depletion of dNTP precursors of DNA, thereby selectively starving fast-replicating cancer cells of nucleotides for survival. The redox-active form of 3-AP directly responsible for inhibition of RNR is the Fe(II)(3-AP) 2 complex. In this work, we synthesize 12 analogs of 3-AP, test their inhibition of RNR in vitro, and study the electronic properties of their iron complexes. The reduction and oxidation events of 3-AP iron complexes that are crucial for the inhibition of RNR are modeled with solution studies. We monitor the pH necessary to induce reduction in iron complexes of 3-AP analogs in a reducing environment, as well as the kinetics of oxidation in an oxidizing environment. The oxidation state of the complex is monitored using UV-Vis spectroscopy. Isoquinoline analogs of 3-AP favor the maintenance of the biologically active reduced complex and possess oxidation kinetics that allow redox cycling, consistent with their effective inhibition of RNR seen in our in vitro experiments. In contrast, methylation on the thiosemicarbazone secondary amine moiety of 3-AP produces analogs that form iron complexes with much higher redox potentials, that do not redox cycle, and are inactive against RNR in vitro. The catalytic subunit of human Ribonucleotide Reductase (RNR), contains a tyrosyl radical in the enzyme active site. Fe(II) complexes of 3-AP and its analogs can quench the radical and, subsequently, inactivate RNR. The potency of RNR inhibitors is highly dependent on the redox properties of the iron complexes, which can be tuned by ligand modifications. Complexes are found to be active within a narrow redox window imposed by the cellular environment.

Mesoporous silica nanoparticles (MSNs) are delivery vehicles that can carry cargo molecules and release them on command. The particles used in the applications reported in this Account are around 100 nm in diameter (about the size of a virus) and contain 2.5 nm tubular pores with a total volume of about 1 cm 3 /g. For the biomedical applications discussed here, the cargo is trapped in the pores until the particles are stimulated to release it. The challenges are to get the particles to the site of a disease and then to deliver the cargo on command. We describe methods to do both, and we illustrate the applicability of the particles to cure cancer and intracellular infectious disease. Our first steps were to design multifunctional nanoparticles with properties that allow them to carry and deliver hydrophobic drugs. Many important pharmaceuticals are hydrophobic and cannot reach the diseased sites by themselves. We describe how we modified MSNs to make them dispersible, imagable, and targetable and discuss in vitro studies. We then present examples of surface modifications that allow them to deliver large molecules such as siRNA. In vivo studies of siRNA delivery to treat triple-negative breast and ovarian cancers are presented. The next steps are to attach nanomachines and other types of caps that trap drug molecules but release them when stimulated. We describe nanomachines that respond autonomously (without human intervention) to stimuli specific to disease sites. A versatile type of machine is a nanovalve that is closed at neutral (blood) pH but opens upon acidification that occurs in endolysosomes of cancer cells. Another type of machine, a snap-top cap, is stimulated by reducing agents such as glutathione in the cytosol of cells. Both of these platforms were studied in vitro to deliver antibiotics to infected macrophages and in vivo to cure and kill the intracellular bacteria M. tuberculosis and F. tularensis. The latter is a tier 1 select agent of bioterrorism. Finally, we describe nanomachines for drug delivery that are controlled by externally administered light and magnetic fields. A futuristic dream for nanotherapy is the ability to control a nano-object everywhere in the body. Magnetic fields penetrate completely and have spatial selectivity governed by the size of the field-producing coil. We describe how to control nanovalves with alternating magnetic fields (AMFs) and superparamagnetic cores inside the MSNs. The AMF heats the cores, and temperature-sensitive caps release the cargo. In vitro studies demonstrate dose control of the therapeutic to cause apoptosis without overheating the cells. Nanocarriers have great promise for therapeutic applications, and MSNs that can carry drugs to the site of a disease to produce a high local concentration without premature release and off-target damage may have the capability of realizing this goal.

Major objectives in nanomedicine and nanotherapy include the ability to trap therapeutic molecules inside of nano-carriers, carry therapeutics to the site of the disease with no leakage, release high local concentrations of drug, release only on demand - either autonomous or external, and kill the cancer cells or an infectious organism. This review will focus on mesoporous silica nanoparticle carriers (MSN) with a large internal pore volume suitable for carrying anticancer and antibiotic drugs, and supramolecular components that function as caps that can both trap and release the drugs on-command. Caps that are especially relevant to this review are rotaxanes and pseudorotaxanes that consist of a long chain-like molecule threaded through a cyclic molecule. Under certain conditions discussed throughout this review, the cyclic molecule can be attracted to one end of the rotaxane and in the presence of a stimulus can slide to the other end. When the thread is attached near the pore opening on MSNs, the sliding cyclic molecule can block the pore when it is near the particle or open it when it slides away. The design, synthesis and operation of supramolecular systems that act as stimuli-responsive pore capping devices that trap and release molecules for therapeutic or imaging applications are discussed. Uncapping can either be irreversible because the cap comes off, or reversible when the cyclic molecule is prevented from sliding off by a steric barrier. In the latter case the amount of cargo released (the dose) can be controlled. These nanomachines act as valves. Examples of supramolecular systems stimulated by chemical signals (pH, redox, enzymes, antibodies) or by external physical signals (light, heat, magnetism, ultrasound) are presented. Many of the systems have been studied in vitro proving that they are taken up by cancer cells and release drugs and kill the cells when stimulated. Some have been studied in mouse models; after IV injection they shrink tumors or kill intracellular pathogens after stimulation. Supramolecular constructs offer fascinating, highly controllable and biologically compatible platforms for drug delivery., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Rationale: Magnetic resonance imaging (MRI) is one of the most widely used diagnostic tools in the clinic. In this setting, real-time monitoring of therapy and tumor site would give the clinicians a handle to observe therapeutic response and to quantify drug amount to optimize the treatment. In this work, we developed a liposome-based cargo (cancer drugs) delivery strategy that could simultaneously monitor the real-time alternating magnetic field-induced cargo release from the change in MRI relaxation parameter R 1 and the location and condition of liposome from the change in R 2 . The tumor site can then be monitored during the cargo release because liposomes would passively target the tumor site through the enhanced permeability and retention (EPR) effect. Physical insights from the experimental results and corresponding Monte Carlo spin dynamics simulations were also discussed. Methods: Superparamagnetic iron oxide (SPIO) nanoparticles, diethylenetriaminepentaacetic acid gadolinium(III) (Gd(III)-DTPA), and a model cancer drug (fluorescein) were co-loaded in PEGylated thermosensitive liposomes. The liposomes were characterized by transmission electron cryo-microscopy (cryoTEM), dynamic light scattering (DLS), and inductively coupled plasma optical emission spectrometry (ICP-OES). Alternating magnetic field (AMF) was used to create controlled mild hyperthermia (39-42°C) and facilitate controlled cargo (fluorescein) release from the thermosensitive liposomes. MRI relaxation parameters, R 1 and R 2 , were measured at room temperature. The temporal variation in R 1 was used to obtain the temporal profile of cargo release. Due to their similar sizes, both the gadolinium and cargo (model cancer drug fluorescein) would come out of the liposomes together as a result of heating. The temporal variation in R 2 was used to monitor SPIO nanoparticles to enhance the tumor contrast. Monte Carlo spin dynamics simulations were performed by solving the Bloch equations and modeling SPIO nanoparticles as magnetized impenetrable spheres. Results: TEM images and DLS measurements showed the diameter of the liposome nanoparticle ~ 200 nm. AMF heating showed effective release of the model drug. It was found that R 1 increased linearly by about 70% and then saturated as the cargo release process was completed, while R 2 remained approximately constant with an initial 7%-drop and then recovered. The linear increase in R 1 is consistent with the expected linear cargo release with time upon AMF heating. Monte Carlo spin dynamics simulations suggest that the initial temporal fluctuation of R 2 is due to the plausible changes of SPIO aggregation and the slow non-recoverable degradation of liposomal membrane that increases water permeability with time by the heating process. The simulations show an order of magnitude increase in R 2 at higher water permeability. Conclusion: We have performed MR parameter study of the release of a cargo (model cancer drug, fluorescein) by magnetic heating from thermosensitive multifunctional liposomes loaded with dual contrast agents. The size of the liposome nanoparticles loaded with model cancer drug (fluorescein), gadolinium chelate, and SPIO nanoparticles was appropriate for a variety of cancer therapies. A careful and detailed analysis with theoretical explanation and simulation was carried out to investigate the correlation between MRI relaxation parameters, R 1 and R 2 , and different cargo release fractions. We have quantified the cargo release using R 1 , which shows a linear relation between each other. This result provides a strong basis for the dosage control of drug delivered. On the other hand, the fairly stable R 2 with almost constant value suggests that it could be used to monitor the position and condition of the liposomal site, as SPIO nanoparticles mostly remained in the aqueous core of the liposome. Because our synthesized SPIO-encapsulated liposomes could be targeted to tumor site passively by the EPR effect, or actively through magnetofection, this study provides a solid ground for developing MR cancer theranostics in combination of this nanostructure and AMF heating strategy. Furthermore, our simulation results predict a sharp increase in R 2 during the AMF heating, which opens up the exciting possibility of high-resolution, high-contrast real-time imaging of the liposomal site during the drug release process, provided AMF heating could be incorporated into an MRI setup. Our use of the clinically approved materials, along with confirmation by theoretical simulations, make this technique a promising candidate for translational MR cancer theranostics., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Noninvasive stimuli-responsive drug delivery using magnetic fields in conjunction with superparamagnetic nanoparticles offers the potential for the spatial and temporal control of drug release. When hyperthermia is not desired and control of the dosage is required, it is necessary to design a platform in which local heating on the nanoscale releases the therapeutic cargo without the bulk heating of the surrounding medium. In this paper, we report a design using a stimuli-responsive nanoparticle platform to control the dosage of the cargo released by an alternating magnetic field (AMF) actuation. A core@shell structure with a superparamagnetic doped iron oxide (MnFe 2 O 4 @CoFe 2 O 4 ) nanoparticle core in a mesoporous silica shell was synthesized. The core used here has a high saturation magnetization value and a high specific loss power for heat generation under an AMF. The mesoporous shell has a high cargo-carrying capacity. A thermoresponsive molecular-based gatekeeper containing an aliphatic azo group was modified on the core@shell nanoparticles to regulate the cargo release. The mesoporous structure of the silica shell remained intact after exposure to an AMF, showing that the release of cargo is due to the removal of the gatekeepers instead of the destruction of the structure. Most importantly, we demonstrated that the amount of cargo released could be adjusted by the AMF exposure time. By applying multiple sequential exposures of AMF, we were able to release the cargo step-wise and increase the total amount of released cargo. In vitro studies showed that the death of pancreatic cancer cells treated by drug-loaded nanoparticles was controlled by different lengths of AMF exposure time due to different amount of drugs released from the carriers. The strategy developed here holds great promise for achieving the dosage, temporal, and spatial control of therapeutics delivery without the risk of overheating the particles' surroundings.

Francisella tularensis causes a serious and often fatal infection, tularemia. We compared the efficacy of moxifloxacin formulated as free drug vs disulfide snap-top mesoporous silica nanoparticles (MSNs) in a mouse model of pneumonic tularemia. We found that MSN-formulated moxifloxacin was more effective than free drug and that the intramuscular and subcutaneous routes were markedly more effective than the intravenous route. Measurement of tissue silica levels and fluorescent flow cytometry assessment of colocalization of MSNs with infected cells revealed that the enhanced efficacy of MSNs and the intramuscular route of delivery was not due to better delivery of MSNs to infected tissues or cells. However, moxifloxacin blood levels demonstrated that the nanoparticle formulation and intramuscular route provided the longest half-life and longest time above the minimal inhibitory concentration. Thus, improved pharmacokinetics are responsible for the greater efficacy of nanoparticle formulation and intramuscular delivery compared with free drug and intravenous delivery.

One-dimensional (1D) metallogels are commonly observed in metal-coordinated complexes, but there are not many examples of soft crystalline solids which are generated by the self-assembly of metal-polymer complexation in a non-gel state. In a continued effort to obtain 1D materials by utilizing the tendency of Pluronic triblock copolymers to be micellized anisotropically at an elevated temperature, we investigate Ag(i)-mediated self-assembly of the surfactant mixture of Pluronic copolymers and cetyltrimethylammonium bromide (CTAB). At sufficiently high temperature, Pluronic copolymers are known to organize into many crystalline mesophases, such as body-centered-cubic, hexagonal, and lamellar phases. Four Pluronics of L-31, L-64, P-123, and F-108 were studied, and at the concentration of 17.9%, macroscale 1D rods with the aspect ratios ranging from 3.07 to 12.8 are obtained. At the concentration of 35.7%, anisotropic two dimensional (2D) planar plates are observed. These planar structures were believed to be generated from 2D lamellar mesophases, which is consistent with the general phase diagram of Pluronic copolymers that shows lamellar phase with the highest concentration. In the absence of ascorbic acid, rods and plates of larger size are produced. Rather than as a reductant, ascorbic acid is thought to play the roles of an agent to increase the hydrophilicity, and as a mediator to determine the dimension of rods and plates by hindering the long range self-assembly of alkyl chains. Dehydration by the addition of AgNO 3 , and the increase of hydrophobicity enable self-assembly of alkyl groups of CTAB and Pluronics and promote the formation of crystalline soft solids., Competing Interests: The author declares no competing financial interest., (This journal is © The Royal Society of Chemistry.)

The use of nanocarriers to deliver poorly soluble drugs to the sites of diseases is an attractive and general method, and mesoporous silica nanoparticles (MSNs) are increasingly being used as carriers. However, both loading a large amount of drugs into the pores and still being able to release the drug is a challenge. In this paper, we demonstrate a general strategy based on a companion molecule that chaperones the drug into the pores and also aids it in escaping. A common related strategy is to use a miscible co-solvent dimethyl sulfoxide (DMSO), but although loading may be efficient in DMSO, this co-solvent frequently diffuses into an aqueous environment, leaving the drug behind. We demonstrate the method by using acetophenone (AP), an FDA-approved food additive as the chaperone for clofazimine (CFZ), a water-insoluble antibiotic used to treat leprosy and multidrug-resistant tuberculosis. AP enables a high amount of CFZ cargo into the MSNs and also carries CFZ cargo out from the MSNs effectively when they are in an aqueous biorelevant environment. The amount of loading and the CFZ release efficiency from MSNs were optimized; 4.5 times more CFZ was loaded in MSNs with AP than that with DMSO and 2300 times more CFZ was released than that without the assistance of the AP. In vitro treatment of macrophages infected by Mycobacterium tuberculosis with the optimized CFZ-loaded MSNs killed the bacteria in the cells in a dose-dependent manner. These studies demonstrate a highly efficient method for loading nanoparticles with water-insoluble drug molecules and the efficacy of the nanoparticles in delivering drugs into eukaryotic cells in aqueous media.

The layer-by-layer technique was exploited to adjust the magnitude of the host⁻guest interactions between adamantane and cyclodextrin. The effect depends on numerous complex and changeable growth profiles of the films and the number of bilayers. These composite films of mesoporous silica nanoparticles and hyaluronic acid⁻cyclodextrin(HA-CD) were constructed to load the fluorescent dyes and peptides. The release rates of these molecules would decrease with an increase in the number of layers. A laser scanning confocal microscope was utilized to obtain the diffusion coefficient of fluorescein isothiocyanate. Hybrid films could be applied to increase the loading of different kinds of molecules and could also be integrated into the lamination to delay the rate of release.

Solid-state electrolytes are the key to the development of lithium-based batteries with dramatically improved energy density and safety. Inspired by ionic channels in biological systems, a novel class of pseudo solid-state electrolytes with biomimetic ionic channels is reported herein. This is achieved by complexing the anions of an electrolyte to the open metal sites of metal-organic frameworks (MOFs), which transforms the MOF scaffolds into ionic-channel analogs with lithium-ion conduction and low activation energy. This work suggests the emergence of a new class of pseudo solid-state lithium-ion conducting electrolytes., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

TWIST protein is critical to development and is activated in many cancers. TWIST regulates epithelial-mesenchymal transition, and is linked to angiogenesis, metastasis, cancer stem cell phenotype, and drug resistance. The majority of epithelial ovarian cancer (EOC) patients with metastatic disease respond well to first-line chemotherapy but most relapse with disease that is both metastatic and drug resistant, leading to a five-year survival rate under 20%. We are investigating the role of TWIST in mediating these relapses. We demonstrate TWIST-siRNA (siTWIST) and a novel nanoparticle delivery platform to reverse chemoresistance in an EOC model. Hyaluronic-acid conjugated mesoporous silica nanoparticles (MSN-HAs) carried siTWIST into target cells and led to sustained TWIST knockdown in vitro. Mice treated with siTWIST-MSN-HA and cisplatin exhibited specific tumor targeting and reduction of tumor burden. This platform has potential application for overcoming clinical challenges of tumor cell targeting, metastasis and chemoresistance in ovarian and other TWIST overexpressing cancers., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Seedless synthesis of Pd nanorods and their self-assembly into the layered smectic ordering are described. Aqueous Pluronic triblock copolymers (14.3-35.7%) are used as a soft template along with cetyltrimethylammonium bromide for inducing one-dimensional growth of Pd nanorods. Pluronic triblock copolymers are probably the most used polymer surfactants, and they are composed of poly(ethylene oxide) (PEO)-poly(propylene oxide) (PPO)-PEO triblocks. Neither pH adjustment nor AgNO 3 and other additives, such as poly(vinyl pyrrolidone) and ethylene glycol, are required to obtain Pd nanorods. Sonochemical synthesis at 43 °C, followed by thermal annealing for 1 h at 65 °C produces Pd nanorods with the aspect ratio from 3.1 (17.9%, Pluronic L-64) to 6.7 (35.7%, Pluronic P-123). Two-dimensional self-assembly of the nanorods is observed, and both nematic ordering between the mesogens and smectic ordering between the layers is identified. Micellar hydrophobic PPO with hydrated PEO coronas are known to self-assemble into many crystalline orders, including cubic, hexagonal, lamellar, and inverse hexagonal mesophases, which extend into cylindrical micelles with increasing temperature. Relatively small size of Pluronic copolymers with regard to general polymers, but rather large size of their micelles and their tendency to organize into crystalline mesophases are thought to contribute to the anisotropic growth of Pd nanorods.

There is significant interest in the development of methods to create hybrid materials that transform capabilities, in particular for Earth-abundant metal oxides, such as TiO 2 , to give improved or new properties relevant to a broad spectrum of applications. Here we introduce an approach we refer to as 'molecular cross-linking', whereby a hybrid molecular boron oxide material is formed from polyhedral boron-cluster precursors of the type [B 12 (OH) 12 ] 2- . This new approach is enabled by the inherent robustness of the boron-cluster molecular building block, which is compatible with the harsh thermal and oxidizing conditions that are necessary for the synthesis of many metal oxides. In this work, using a battery of experimental techniques and materials simulation, we show how this material can be interfaced successfully with TiO 2 and other metal oxides to give boron-rich hybrid materials with intriguing photophysical and electrochemical properties.

Coherent two-photon-excited (TPE) therapy in the near-infrared (NIR) provides safer cancer treatments than current therapies lacking spatial and temporal selectivities because it is characterized by a 3D spatial resolution of 1 µm 3 and very low scattering. In this review, the principle of TPE and its significance in combination with organosilica nanoparticles (NPs) are introduced and then studies involving the design of pioneering TPE-NIR organosilica nanomaterials are discussed for bioimaging, drug delivery, and photodynamic therapy. Organosilica nanoparticles and their rich and well-established chemistry, tunable composition, porosity, size, and morphology provide ideal platforms for minimal side-effect therapies via TPE-NIR. Mesoporous silica and organosilica nanoparticles endowed with high surface areas can be functionalized to carry hydrophobic and biologically unstable two-photon absorbers for drug delivery and diagnosis. Currently, most light-actuated clinical therapeutic applications with NPs involve photodynamic therapy by singlet oxygen generation, but low photosensitizing efficiencies, tumor resistance, and lack of spatial resolution limit their applicability. On the contrary, higher photosensitizing yields, versatile therapies, and a unique spatial resolution are available with engineered two-photon-sensitive organosilica particles that selectively impact tumors while healthy tissues remain untouched. Patients suffering pathologies such as retinoblastoma, breast, and skin cancers will greatly benefit from TPE-NIR ultrasensitive diagnosis and therapy., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In the version of this Article originally published, Liban M. A. Saleh was incorrectly listed as Liban A. M. Saleh due to a technical error. This has now been amended in all online versions of the Article.

In this review we focus on methods that are used to trap and release on command therapeutic drugs from mesoporous silica nanoparticles (MSNs). The pores in the MSNs are large enough to accommodate a wide range of cargo molecules such as anticancer and antibiotic drugs and yet small enough to be blocked by a variety of bulky molecules that act as caps. The caps are designed to be tightly attached to the pore openings and trap the cargo molecules without leakage, but upon application of a designed stimulus detach from the nanoparticles and release the cargo. Of special emphasis in this review are nanomachines that respond to stimuli administered from external sources such as light or magnetic fields, or from chemical stimuli produced by the biological system such as a general change in pH or redox potential, or a highly specific chemical produced by a cancer cell or infectious bacterium. The goal is to release a high local concentration of the cargo only where and when it is needed, thus minimizing off-target side effects. We discuss sophisticated reversible nanomachines but also discuss some useful caps that simply break off from the nanoparticles in response to the selected stimulus. Many ingenious systems have been and are being designed; we primarily highlight those that have been demonstrated to operate in vitro and/or in vivo. In most cases the closed MSNs are endocytosed by diseased or infected cells and opened inside the cells to release the drugs. We begin with an overview of the nanoparticles and nanomachines and then present examples of drug release triggered by internal chemical stimuli from the organism and finally by external light and magnetic field stimuli., (© 2018 Elsevier Inc. All rights reserved.)

Bean (Phaseolus vulgaris) plants were grown for 45 days in soil amended with either uncoated (Z-COTE ® ) and coated (Z-COTE HP1 ® ) ZnO nanomaterials (NMs), bulk ZnO and ZnCl 2 , at 0-500mg/kg. At harvest, growth parameters, chlorophyll, and essential elements were determined. None of the treatments affected germination and pod production, and only ZnCl 2 at 250 and 500mg/kg reduced relative chlorophyll content by 34% and 46%, respectively. While Z-COTE ® did not produce phenotypic changes, Z-COTE HP1 ® , at all concentrations, increased root length (∼44%) and leaf length (∼13%) compared with control. Bulk ZnO reduced root length (53%) at 62.5mg/kg and ZnCl 2 reduced leaf length (16%) at 125mg/kg. Z-COTE ® , at 125mg/kg, increased Zn by 203%, 139%, and 76% in nodules, stems, and leaves, respectively; while at the same concentration, Z-COTE HP1 ® increased Zn by 89%, 97%, and 103% in roots, stems, and leaves, respectively. At 125mg/kg, Z-COTE HP1 ® increased root S (65%) and Mg (65%), while Z-COTE ® increased stem B (122%) and Mn (73%). Bulk ZnO and ZnCl 2 imposed more toxicity to kidney bean than the NMs, since they reduced root and leaf elongation, respectively, and the concentration of several essential elements in tissues., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We present a synthetic approach to a highly pathogen-selective detection and delivery platform based on the interaction of an antibody nanovalve with a tetrasaccharide from the O-antigen of the lipopolysaccharide (LPS) of Francisella tularensis bacteria, a Tier 1 Select Agent of bioterrorism. Different design considerations are explored, and proof-of-concept for highly pathogen-specific cargo release from mesoporous silica nanoparticles is demonstrated by comparisons of the release of a signal transducer and model drug by LPS from F. tularensis vs Pseudomonas aeruginosa and by F. tularensis live bacteria vs the closely related bacterium Francisella novocida. In addition to the specific response to a biowarfare agent, treatment of infectious diseases in general could benefit tremendously from a delivery platform that releases its antibiotic payload only at the site of infection and only in the presence of the target pathogen, thereby minimizing off-target toxicities.

Epithelial ovarian cancer (EOC) is the most deadly gynecologic malignancy on account of its late stage at diagnosis and frequency of drug resistant recurrences. Novel therapies to overcome these barriers are urgently needed. TWIST is a developmental transcription factor reactivated in cancers and linked to angiogenesis, metastasis, cancer stem cell phenotype, and drug resistance, making it a promising therapeutic target. In this work, we demonstrate the efficacy of TWIST siRNA (siTWIST) and two nanoparticle delivery platforms to reverse chemoresistance in EOC models. Polyamidoamine dendrimers and mesoporous silica nanoparticles (MSNs) carried siTWIST into target cells and led to sustained TWIST knockdown in vitro. Mice treated with cisplatin plus MSN-siTWIST exhibited lower tumor burden than mice treated with cisplatin alone, with most of the effect coming from reduction in disseminated tumors. This platform has potential application for overcoming the clinical challenges of metastasis and chemoresistance in EOC and other TWIST overexpressing cancers., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Little is known about the effects of surface coating on the interaction of engineered nanoparticles (ENPs) with plants. In this study, basil (Ocimum basilicum) was cultivated for 65 days in soil amended with unmodified, hydrophobic (coated with aluminum oxide and dimethicone), and hydrophilic (coated with aluminum oxide and glycerol) titanium dioxide nanoparticles (nano-TiO 2 ) at 125, 250, 500, and 750 mg nano-TiO 2 kg -1 soil. ICP-OES/MS, SPAD meter, and UV/Vis spectrometry were used to determine Ti and essential elements in tissues, relative chlorophyll content, carbohydrates, and antioxidant response, respectively. Compared with control, hydrophobic and hydrophilic nano-TiO 2 significantly reduced seed germination by 41% and 59%, respectively, while unmodified and hydrophobic nano-TiO 2 significantly decreased shoot biomass by 31% and 37%, respectively (p ≤ 0.05). Roots exposed to hydrophobic particles at 750 mg kg -1 had 87% and 40% more Ti than the pristine and hydrophilic nano-TiO 2 ; however, no differences were found in shoots. The three types of particles affected the homeostasis of essential elements: at 500 mg kg - 1 , unmodified particles increased Cu (104%) and Fe (90%); hydrophilic increased Fe (90%); while hydrophobic increased Mn (339%) but reduced Ca (71%), Cu (58%), and P (40%). However, only hydrophobic particles significantly reduced root elongation by 53%. Unmodified, hydrophobic, and hydrophilic particles significantly reduced total sugar by 39%, 38%, and 66%, respectively, compared with control. Moreover, unmodified particles significantly decreased reducing sugar (34%), while hydrophobic particles significantly reduced starch (35%). Although the three particles affected basil plants, coated particles impacted the most its nutritional quality, since they altered more essential elements, starch, and reducing sugars., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A multifunctional nanoparticle with designed selectivity was made using hollow mesoporous silica, ship-in-a-bottle synthesis of a crystalline solid-state detector, and protection of the crystal by acid-responsive nanogates. The system demonstrates the inverse application of the usual trapping of contents by the gate followed by their release. Instead, the gate protects the contents followed by selective exposure. Crystallization of [Pt(tpy)Cl](PF 6 ) (tpy = 2,2':6',2''-terpyridine) inside the cavity of hollow mesoporous silica created the unique core/shell nanoparticle. The crystalline core becomes fluorescent in the presence of perchlorate. By condensing an acid-sensitive gate onto the particle, access to the pores is blocked and the crystal is protected. The new nanomaterial obeys Boolean AND logic; only the presence of both the analyte (ClO 4 - ) and acid results in the optical response.

We describe biodegradable mesoporous hybrid nanoparticles (NPs) in the presence of proteins and their applications for drug delivery. We synthesized oxamide phenylene-based mesoporous organosilica nanoparticles (MON) in the absence of a silica source which had remarkably high organic content and high surface areas. Oxamide functions provided biodegradability in the presence of trypsin model proteins. MON displayed exceptionally high payloads of hydrophilic and hydrophobic drugs (up to 84 wt %), and a unique zero premature leakage without the pore capping, unlike mesoporous silica. MON were biocompatible and internalized into cancer cells for drug delivery., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Creation of structural complexity by simple experimental control will be an attractive approach for the preparation of nanomaterials, as a classical bottom-up method is supplemented by a more efficient and more direct artificial engineering method. In this study, structural manipulation of MCM-41 type mesoporous silica is investigated by generating and imbedding hard magnetic CoFe2O4 nanoparticles into mesoporous silica. Depending on the heating rate and target temperature, mesoporous silica undergoes a transformation in shape to form hollow silica, framed silica with interior voids, or melted silica with intact mesostructures. Magnetism is governed by the major CoFe2O4 phase, and it is affected by antiferromagnetic hematite (α-Fe2O3) and olivine-type cobalt silicate (Co2SiO4), as seen in its paramagnetic behavior at the annealing temperature of 430 °C. The early formation of Co2SiO4 than what is usually observed implies the effect of the partial substitution of Fe in the sites of Co. Under slow heating (2.5 °C min(-1)) mesostructures are preserved, but with significantly smaller mesopores (d100 = 1.5 nm). In addition, nonstoichiometric CoxFe1-xO with metal vacancies at 600 °C, and spinel Co3O4 at 700 °C accompany major CoFe2O4. The amorphous nature of silica matrix is thought to contribute significantly to these structurally diverse and rich phases, enabled by off-stoichiometry between Si and O, and accelerated by the diffusion of metal cations into SiO4 polyhedra at an elevated temperature.

Bis(clickable) mesoporous silica nanospheres (ca. 100 nm) were obtained by the co-condensation of TEOS with variable amounts (2-5 % each) of two clickable organosilanes in the presence of CTAB. Such nanoparticles could be easily functionalized with two independent functions using the copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction to transform them into nanomachines bearing cancer cell targeting ligands with the ability to deliver drugs on-demand. The active targeting was made possible after anchoring folic acid by CuAAC click reaction, whereas the controlled delivery was performed by clicked azobenzene fragments. Indeed, the azobenzene groups are able to obstruct the pores of the nanoparticles in the dark whereas upon irradiation in the UV or in the blue range, their trans-to-cis photoisomerization provokes disorder in the pores, enabling the delivery of the cargo molecules. The on-command delivery was proven in solution by dye release experiments, and in vitro by doxorubicin delivery. The added value of the folic acid ligand was clearly evidenced by the difference of cell killing induced by doxorubicin-loaded nanoparticles under blue irradiation, depending on whether the particles featured the clicked folic acid ligand or not., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Despite the worldwide interest generated by periodic mesoporous organosilica (PMO) bulk materials, the design of PMO nanomaterials with controlled morphology remains largely unexplored and their properties unknown. In this work, we describe the first study of PMO nanoparticles (NPs) based on meta-phenylene bridges, and we conducted a comparative structure-property relationship investigation with para-phenylene-bridged PMO NPs. Our findings indicate that the change of the isomer drastically affects the structure, morphology, size, porosity and thermal stability of PMO materials. We observed a much higher porosity and thermal stability of the para-based PMO which was likely due to a higher molecular periodicity. Additionally, the para isomer could generate multipodal NPs at very low stirring speed and upon this discovery we designed a phenylene-ethylene bridged PMO with a controlled Janus morphology. Unprecedentedly high payloads could be obtained from 40 to 110 wt % regardless of the organic bridge of PMOs. Finally, we demonstrate for the first time the co-delivery of two cargos by PMO NPs. Importantly, the cargo stability in PMOs did not require the capping of the pores, unlike pure silica, and the delivery could be autonomously triggered in cancer cells by acidic pH with nearly 70 % cell killing., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Effective and rapid treatment of tularemia is needed to reduce morbidity and mortality of this potentially fatal infectious disease. The etiologic agent, Francisella tularensis, is a facultative intracellular bacterial pathogen which infects and multiplies to high numbers in macrophages. Nanotherapeutics are particularly promising for treatment of infectious diseases caused by intracellular pathogens, whose primary host cells are macrophages, because nanoparticles preferentially target and are avidly internalized by macrophages. A mesoporous silica nanoparticle (MSN) has been developed functionalized with disulfide snap-tops that has high drug loading and selectively releases drug intracellularly in response to the redox potential. These nanoparticles, when loaded with Hoechst fluorescent dye, release their cargo exclusively intracellularly and stain the nuclei of macrophages. The MSNs loaded with moxifloxacin kill F. tularensis in macrophages in a dose-dependent fashion. In a mouse model of lethal pneumonic tularemia, MSNs loaded with moxifloxacin prevent weight loss, illness, and death, markedly reduce the burden of F. tularensis in the lung, liver, and spleen, and are significantly more efficacious than an equivalent amount of free drug. An important proof-of-principle for the potential therapeutic use of a novel nanoparticle drug delivery platform for the treatment of infectious diseases is provided., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Many machines (including nanomachines) consist of a solid support with moving parts that can undergo large amplitude motion to carry out specific tasks. In this Minireview, we will describe nanomachines that are supported on mesoporous silica nanoparticles that are typically 50-100 nanometers in diameter and have an array of open, readily accessible pores with an average width of a few nanometers. For triggering a large amplitude motion of the moving parts, we will focus primarily on external stimuli such as heat or light. As for the specific task the machines are carrying out, this Minireview will focus on the controlled release of pharmaceutically active agents in biomedical applications. We will discuss examples of how nanomachines can be used for remotely controlled cargo release and how existing machines that were originally designed to respond to internal physiological stimuli could be reconfigured to respond to external stimuli instead., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Temperature changes initiated within nano structures are being increasingly used to externally activate responsive delivery vehicles. Yet, the precise measurement of the nano environment temperature increase and its correlation with the induced macroscopic cargo release are difficult to achieve. In this study, we focus on a photothermally activated drug delivery system based on mesoporous silica nanoparticles, and use an optical nanothermometer - NaYF4:Yb(3+),Er(3+) crystals - for a ratiometric temperature measurement. Using fluorescent dyes as the payload molecule, both the nanoparticle interior temperature change and the macroscopic cargo release amount are monitored simultaneously by fluorescent spectroscopy. We found that the cargo release lags the temperature increase by about 5 min, revealing the threshold temperature that the particles have to reach before a substantial release could happen. Using this spectroscopic method, we are able to directly compare and correlate a nano environment event with its stimulated macroscopic results.

Functional nanocarriers capable of transporting high drug contents without premature leakage and to controllably deliver several drugs are needed for better cancer treatments. To address this clinical need, gold cluster bovine serum albumin (AuNC@BSA) nanogates were engineered on mesoporous silica nanoparticles (MSN) for high drug loadings and co-delivery of two different anticancer drugs. The first drug, gemcitabine (GEM, 40wt%), was loaded in positively-charged ammonium-functionalized MSN (MSN-NH3(+)). The second drug, doxorubicin (DOX, 32wt%), was bound with negatively-charged AuNC@BSA electrostatically-attached onto MSN-NH3(+), affording highly loaded pH-responsive MSN-AuNC@BSA nanocarriers. The co-delivery of DOX and GEM was achieved for the first time via an inorganic nanocarrier, possessing a zero-premature leakage behavior as well as drug loading capacities seven times higher than polymersome NPs. Besides, unlike the majority of strategies used to cap the pores of MSN, AuNC@BSA nanogates are biotools and were applied for targeted red nuclear staining and in-vivo tumor imaging. The straightforward non-covalent combination of MSN and gold-protein cluster bioconjugates thus leads to a simple, yet multifunctional nanotheranostic for the next generation of cancer treatments., (Copyright © 2016. Published by Elsevier B.V.)

A facile, reproducible, and scalable method was explored to construct uniform Au@poly(acrylic acid) (PAA) Janus nanoparticles (JNPs). The as-prepared JNPs were used as templates to preferentially grow a mesoporous silica (mSiO2 ) shell and Au branches separately modified with methoxy-poly(ethylene glycol)-thiol (PEG) to improve their stability, and lactobionic acid (LA) for tumor-specific targeting. The obtained octopus-type PEG-Au-PAA/mSiO2 -LA Janus NPs (PEG-OJNP-LA) possess pH and NIR dual-responsive release properties. Moreover, DOX-loaded PEG-OJNP-LA, upon 808 nm NIR light irradiation, exhibit obviously higher toxicity at the cellular and animal levels compared with chemotherapy or photothermal therapy alone, indicating the PEG-OJNP-LA could be utilized as a multifunctional nanoplatform for in vitro and in vivo actively-targeted and chemo-photothermal cancer therapy., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We have optimized mesoporous silica nanoparticles (MSNs) functionalized with pH-sensitive nanovalves for the delivery of the broad spectrum fluoroquinolone moxifloxacin (MXF) and demonstrated its efficacy in treating Francisella tularensis infections both in vitro and in vivo. We compared two different nanovalve systems, positive and negative charge modifications of the mesopores, and different loading conditions-varying pH, cargo concentration, and duration of loading-and identified conditions that maximize both the uptake and release capacity of MXF by MSNs. We have demonstrated in macrophage cell culture that the MSN-MXF delivery platform is highly effective in killing F. tularensis in infected macrophages, and in a mouse model of lethal pneumonic tularemia, we have shown that the drug-loaded MSNs are much more effective in killing F. tularensis than an equivalent amount of free MXF.

On page 5066, J. I. Zink, M. A. Horwitz, and co-workers use confocal microscopy to demonstrate the avid uptake of RITC-labeled mesoporous silica nanoparticles loaded with the anti-tuberculosis drug isoniazid (shown here in red) by human macrophages (nuclei stained blue with DAPI) infected with GFP-expressing Mycobacterium tuberculosis (shown here in green)., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Growth and progression of solid tumors depend on the integration of multiple pro-growth and survival signals, including the induction of angiogenesis. TWIST1 is a transcription factor whose reactivation in tumors leads to epithelial to mesenchymal transition (EMT), including increased cancer cell stemness, survival, and invasiveness. Additionally, TWIST1 drives angiogenesis via activation of IL-8 and CCL2, independent of VEGF signaling. In this work, results suggest that chemically modified siRNA against TWIST1 reverses EMT both in vitro and in vivo. siRNA delivery with a polyethyleneimine-coated mesoporous silica nanoparticle (MSN) led to reduction of TWIST1 target genes and migratory potential in vitro. In mice bearing xenograft tumors, weekly intravenous injections of the siRNA-nanoparticle complexes resulted in decreased tumor burden together with a loss of CCL2 suggesting a possible anti-angiogenic response. Therapeutic use of TWIST1 siRNA delivered via MSNs has the potential to inhibit tumor growth and progression in many solid tumor types., From the Clinical Editor: Tumor progression and metastasis eventually lead to patient mortality in the clinical setting. In other studies, it has been found that TWIST1, a transcription factor, if reactivated in tumors, would lead to downstream events including angiogenesis and result in poor prognosis in cancer patients. In this article, the authors were able to show that when siRNA against TWIST1 was delivered via mesoporous silica nanoparticle, there was tumor reduction in an in-vivo model. The results have opened up a new avenue for further research in this field., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Tuberculosis is a major global health problem for which improved therapeutics are needed to shorten the course of treatment and combat emergence of drug resistance. Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is an intracellular pathogen of mononuclear phagocytes. As such, it is an ideal pathogen for nanotherapeutics because macrophages avidly ingest nanoparticles even without specific targeting molecules. Hence, a nanoparticle drug delivery system has the potential to target and deliver high concentrations of drug directly into M. tuberculosis-infected cells-greatly enhancing efficacy while avoiding off-target toxicities. Stimulus-responsive mesoporous silica nanoparticles of two different sizes, 100 and 50 nm, are developed as carriers for the major anti-tuberculosis drug isoniazid in a prodrug configuration. The drug is captured by the aldehyde-functionalized nanoparticle via hydrazone bond formation and coated with poly(ethylene imine)-poly(ethylene glycol) (PEI-PEG). The drug is released from the nanoparticles in response to acidic pH at levels that naturally occur within acidified endolysosomes. It is demonstrated that isoniazid-loaded PEI-PEG-coated nanoparticles are avidly ingested by M. tuberculosis-infected human macrophages and kill the intracellular bacteria in a dose-dependent manner. It is further demonstrated in a mouse model of pulmonary tuberculosis that the nanoparticles are well tolerated and much more efficacious than an equivalent amount of free drug., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Nanoimpellers are mesoporous silica nanoparticles that contain azobenzene derivatives bonded inside the pores and rely on the continuous photoisomerization of multiple azobenzenes to release cargo under near UV irradiation. A recent study employs upconversion nanocrystal embedded particles to replace UV light with IR light to stimulate nanoimpellers. However, the photothermal effect of IR irradiation and its likely contribution to the observed release behavior are not examined. It is found that, in the absence of upconversion nanocrystals, the azobenzene co-condensed silica particles still respond to 980 nm illumination, which increases the nanoparticle temperature by 25 °C in 15 min, experimentally measured by an encapsulated nanothermometer. After suppressing the heating, the IR irradiation does not initiate the release, indicating that optical heating, not upconverted light, is responsible for the triggered cargo release. The results are explained by numerical analyses., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)