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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 Fe3O4or MnFe2O4core 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 MnFe2O4fluorous ferrofluid has the highest combination of stability and magnetization reported to date.

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., MnFe2O4@CoFe2O4@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.

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.

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 (Hor G), the drug-loading H+Gcoassemblies (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 vivoimplantation 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 rvalue 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 IC50values in the low-to-mid nanomolar range. Density functional theory (DFT) calculations showed that fluorination at the 6-position of HCT-13was 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-13treatment. We further show that the cytotoxicity of HCT-13is 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 vivoefficacy of HCT-13against aggressive models of acute leukemias in mice.

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 T1was 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.

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 vivowith 980 nm excitation.

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 cm3/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.

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 (MnFe2O4@CoFe2O4) 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 vitrostudies 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.

Mesoporous silica nanoparticles are useful nanomaterials that have demonstrated the ability to contain and release cargos with mediation by gatekeepers. Magnetic nanocrystals have the ability to exhibit hyperthermic effects when placed in an oscillating magnetic field. In a system combining these two materials and a thermally sensitive gatekeeper, a unique drug delivery system can be produced. A novel material that incorporates zinc-doped iron oxide nanocrystals within a mesoporous silica framework that has been surface-modified with pseudorotaxanes is described. Upon application of an AC magnetic field, the nanocrystals generate local internal heating, causing the molecular machines to disassemble and allowing the cargos (drugs) to be released. When breast cancer cells (MDA-MB-231) were treated with doxorubicin-loaded particles and exposed to an AC field, cell death occurred. This material promises to be a noninvasive, externally controlled drug delivery system with cancer-killing properties.

Pancreatic ductal adenocarcinoma (PDAC) elicits a dense stromal response that blocks vascular access because of pericyte coverage of vascular fenestrations. In this way, the PDAC stroma contributes to chemotherapy resistance in addition to causing other problems. In order to improve the delivery of gemcitabine, a first-line chemotherapeutic agent, a PEGylated drug-carrying liposome was developed, using a transmembrane ammonium sulfate gradient to encapsulate the protonated drug up to 20% w/w. However, because the liposome was precluded from entering the xenograft site due to the stromal interference, we developed a first-wave nanocarrier that decreases pericyte coverage of the vasculature through interference in the pericyte recruiting TGF-β signaling pathway. This was accomplished using a polyethyleneimine (PEI)/polyethylene glycol (PEG)-coated mesoporous silica nanoparticle (MSNP) for molecular complexation to a small molecule TGF-β inhibitor, LY364947. LY364947 contains a nitrogen atom that attaches, through H-bonding, to PEI amines with a high rate of efficiency. The copolymer coating also facilitates systemic biodistribution and retention at the tumor site. Because of the high loading capacity and pH-dependent LY364947 release from the MSNPs, we achieved rapid entry of IV-injected liposomes and MSNPs at the PDAC tumor site. This two-wave approach provided effective shrinkage of the tumor xenografts beyond 25 days, compared to the treatment with free drug or gemcitabine-loaded liposomes only. Not only does this approach overcome stromal resistance to drug delivery in PDAC, but it also introduces the concept of using a stepwise engineered approach to address a range of biological impediments that interfere in nanocancer therapy in a spectrum of cancers.

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 tuberculosiswith 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.

Oxygen vacancies are prevalent in amorphous silica. It is recently recognized that the diffusion of metal cations and hydrolytic weakening at the elevated temperature produced hollow framed silica with interior voids. Electron energy-loss spectroscopy (EELS) reveals more complex behaviors of metals and oxygen underneath this seemingly simple shape evolution. In Fe3O4/SiO2nanocomposites, polyhedral distortion is severe, and the alteration of Si–O–Si bonding occurs. Ionic character is strengthened, and the oxidation number of Si decreases with increasing annealing temperature. Despite this distortion, ordering of oxygen within amorphous silica is enhanced with the increase of annealing temperature. Reduction of Fe3+to Fe2+is also facilitated by the diffusion of Fe3+into SiO4tetrahedra. In the presence of Co, however, polyhedral distortion is not severe, and it is supposed that Co not only resides on the surface of mesoporous silica but also inhibits the diffusion of Fe into SiO4tetrahedra. In addition, Co suppresses the formation of Fe3O4and other iron oxides, and it also retards the formation of CoFe2O4. Despite the shape reorganization in CoFe2O4/SiO2nanocomposites, the covalent nature of SiO4tetrahedra is maintained throughout the annealing temperature. Under the slow heating process (2.5 °C/min), however, the diffusion of Fe and Co is enhanced, and they undergo amorphous alloying with Si. Without making crystalline CoFe2O4, this alloying contributes to the formation of metallic Si. All these observations are governed by oxygen deficiency in amorphous silica and the enhanced diffusion of transition metal cations at the elevated temperature.

Mesoporous silica nanoparticles have been widely used as molecular containers. Properties of molecules trapped in the pores of the nanoparticles are not yet comprehensively understood. This work quantitatively studied molecular motions of guest compounds in mesoporous silica nanoparticles by calculating rotational correlation times from spin–lattice relaxation measured using solid-state NMR. The effect of pore wall charge and probe molecule size on molecular motion inside nanoparticles was proven to significantly change the molecular dynamics in a confined space.

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.

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 tularensisinfections both in vitroand 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. tularensisin 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. tularensisthan an equivalent amount of free MXF.

Copper formulations have been used for decades for antimicrobial and antifouling applications. With the development of nanoformulations of copper that are more effective than their ionic and microsized analogues, a key regulatory question is whether these materials should be treated as new or existing materials. To address this issue, here we compare the magnitude and mechanisms of toxicity of a series of Cu species (at concentration ranging from 2 to 250 μg/mL), including nano Cu, nano CuO, nano Cu(OH)2(CuPro and Kocide), micro Cu, micro CuO, ionic Cu2+(CuCl2and CuSO4) in two species of bacteria (Escherichia coliand Lactobacillus brevis). The primary size of the particles studied ranged from 10 nm to 10 μm. Our results reveal that Cu and CuO nanoparticles (NPs) are more toxic than their microsized counterparts at the same Cu concentration, with toxicities approaching those of the ionic Cu species. Strikingly, these NPs showed distinct differences in their mode of toxicity when compared to the ionic and microsized Cu, highlighting the unique toxicity properties of materials at the nanoscale. In vitroDNA damage assays reveal that both nano Cu and microsized Cu are capable of causing complete degradation of plasmid DNA, but electron tomography results show that only nanoformulations of Cu are internalized as intact intracellular particles. These studies suggest that nano Cu at the concentration of 50 μg/mL may have unique genotoxicity in bacteria compared to ionic and microsized Cu.

Upconversion nanoparticles (UCNPs), which are generated by doping with rare earth (RE) metals, are increasingly used for bioimaging because of the advantages they hold over conventional fluorophores. However, because pristine RE nanoparticles (NPs) are unstable in acidic physiological fluids (e.g., lysosomes), leading to intracellular phosphate complexation with the possibility of lysosomal injury, it is important to ensure that UCNPs are safely designed. In this study, we used commercially available NaYF4:Er/Yb UCNPs to study their stability in lysosomes and simulated lysosomal fluid. We demonstrate that phosphate complexation leads to REPO4deposition on the particle surfaces and morphological transformation. This leads to a decline in upconversion fluorescence efficiency as well as inducing pro-inflammatory effects at the cellular level and in the intact lung. In order to preserve the imaging properties of the UCNPs as well as improve their safety, we experimented with a series of phosphonate chemical moieties to passivate particle surfaces through the strong coordination of the organophosphates with RE atoms. Particle screening and physicochemical characterization revealed that ethylenediamine tetra(methylenephosphonic acid) (EDTMP) surface coating provides the most stable UCNPs, which maintain their imaging intensity and do not induce pro-inflammatory effects in vitroand in vivo. In summary, phosphonate coating presents a safer design method that preserves and improves the bioimaging properties of UCNPs, thereby enhancing their biological use.