Synergistic Targeting and Efficient Photodynamic Therapy Based on Graphene Oxide Quantum Dot‐Upconversion Nanocrystal Hybrid Nanoparticles

Locating nanotherapeutics at the active sites, especially in the subcellular scale, is of great importance for nanoparticle‐based photodynamic therapy (PDT) and other nanotherapies. However, subcellular targeting agents are generally nonspecific, despite the fact that the accumulation of a nanoformulation at active organelles leads to better therapeutic efficacy. A PDT nanoformulation is herein designed by using graphene oxide quantum dots (GOQDs) with rich functional groups as both the supporter for dual targeting modification and the photosensitizer for generating reactive oxygen species, and upconversion nanoparticles (UCNs) as the transducer of excitation light. A tumor‐targeting agent, folic acid, and a mitochondrion‐targeting moiety, carboxybutyl triphenylphosphonium, are simultaneously attached onto the UCNs–GOQDs hybrid nanoparticles by surface modification, and a synergistic targeting effect is obtained for these nanoparticles according to both in vitro and in vivo experiments. More significant cell death and a higher extent of mitochondrion damage are observed compared to the results of UCNs–GOQDs nanoparticles with no or just one targeting moiety. Furthermore, the PDT efficacy on tumor‐bearing mice is also effectively improved. Overall, the current work presents a synergistic strategy to enhance subcellular targeting and the PDT efficacy for cancer therapy, which may also shed light on other kinds of nanotherapies.     

A Modular System for the Design of Stimuli‐Responsive Multifunctional Nanoparticle Aggregates by Use of Host–Guest Chemistry

A self‐assembly approach for the design of multifunctional nanomaterials consisting of different nanoparticles (gold, iron oxide, and lanthanide‐doped LiYF₄) is developed. This modular system takes advantage of the light‐responsive supramolecular host–guest chemistry of β‐cyclodextrin and arylazopyrazole, which enables the dynamic and reversible self‐assembly of particles to spherical nanoparticle aggregates in aqueous solution. Due to the magnetic iron oxide nanoparticles, the aggregates can be manipulated by an external magnetic field leading to the formation of linear structures. As a result of the integration of upconversion nanoparticles, the aggregates are additionally responsive to near‐infrared light and can be redispersed by use of the upconversion effect. By varying the nanoparticle and linker concentrations the composition, size, shape, and properties of the multifunctional nanoparticle aggregates can be fine‐tuned.     

Quasi‐Continuous Wave Near‐Infrared Excitation of Upconversion Nanoparticles for Optogenetic Manipulation of C. elegans

Optogenetics is an emerging powerful tool to investigate workings of the nervous system. However, the use of low tissue penetrating visible light limits its therapeutic potential. Employing deep penetrating near‐infrared (NIR) light for optogenetics would be beneficial but it cannot be used directly. This issue can be tackled with upconversion nanoparticles (UCNs) acting as nanotransducers emitting at shorter wavelengths extending to the UV range upon NIR light excitation. Although attractive, implementation of such NIR‐optogenetics is hindered by the low UCN emission intensity that necessitates high NIR excitation intensities, resulting in overheating issues. A novel quasi‐continuous wave (quasi‐CW) excitation approach is developed that significantly enhances multiphoton emissions from UCNs, and for the first time NIR light‐triggered optogenetic manipulations are implemented in vitro and in C. elegans. The approach developed here enables the activation of channelrhodopsin‐2 with a significantly lower excitation power and UCN concentration along with negligible phototoxicity as seen with CW excitation, paving the way for therapeutic optogenetics.     

ZnO Film UV Photodetector with Enhanced Performance: Heterojunction with CdMoO4 Microplates and the Hot Electron Injection Effect of Au Nanoparticles

A novel CdMoO₄–ZnO composite film is prepared by spin‐coating CdMoO₄ microplates on ZnO film and is constructed as a heterojunction photodetector (PD). With an optimized loading amount of CdMoO₄ microplates, this composite film PD achieves a ≈18‐fold higher responsivity than pure ZnO film PD at 5 V bias under 350 nm (0.15 mW cm⁻²) UV light illumination, and its decay time shortens to half of the original value. Furthermore, Au nanoparticles are then deposited to modify the CdMoO₄–ZnO composite film, and the as‐constructed photodetector with an optimized deposition time of Au nanoparticles yields an approximately two‐fold higher photocurrent under the same condition, and the decay time reduces by half. The introduced CdMoO₄ microplates form type‐II heterojunctions with ZnO film and improve the photoelectric performance. The hot electrons from Au nanoparticles are injected into the CdMoO₄–ZnO composite film, leading to the increased photocurrent. When the light is off, the Schottky barriers formed between Au nanoparticles and CdMoO₄–ZnO composite film block the carrier transportation and accelerate the decay process of current. The study on Au‐nanoparticle‐modified CdMoO₄–ZnO composite film provides a facile method to construct ZnO film based PD with novel structure and high photoelectric performance.     

A Monodispersed Spherical Zr‐Based Metal–Organic Framework Catalyst,Pt/Au@Pd@UIO‐66, Comprising an Au@Pd Core–Shell Encapsulated in a UIO‐66 Center and Its Highly Selective CO2 Hydrogenation to Produce CO

A Zr‐based metal–organic framework (MOF) catalyst, Pt/Au@Pd@UIO‐66, is assembled, where UIO‐66 is Zr₆O₄(OH)₄(BDC)₆ (BDC = 1,4‐benzenedicarboxylate). The gold nanoparticles (NPs) act as the core for the epitaxial growth of Pd shells, and the core–shell monodispersed nanosphere Au@Pd is encapsulated into UIO‐66 to control its morphology and impart nanoparticle functionality. The microporous nature of UIO‐66 assists the adsorption of Pt NPs, which in turn enhances the interaction between NPs and UIO‐66, favoring the formation of isolated and well‐dispersed Pt NP active sites. This MOF exhibits high catalytic activity and CO product selectivity for the reverse‐water–gas‐shift reaction in a fixed‐bed flow reactor.     

“Dual‐Template” Synthesis of One‐Dimensional Conductive Nanoparticle Superstructures from Coordination Metal–Peptide Polymer Crystals

Bottom‐up fabrication of self‐assembled structures made of nanoparticles may lead to new materials, arrays and devices with great promise for myriad applications. Here a new class of metal–peptide scaffolds is reported: coordination polymer Ag(I)‐DLL belt‐like crystals, which enable the dual‐template synthesis of more sophisticated nanoparticle superstructures. In these biorelated scaffolds, the self‐assembly and recognition capacities of peptides and the selective reduction of Ag(I) ions to Ag are simultaneously exploited to control the growth and assembly of inorganic nanoparticles: first on their surfaces, and then inside the structures themselves. The templated internal Ag nanoparticles are well confined and closely packed, conditions that favour electrical conductivity in the superstructures. It is anticipated that these Ag(I)‐DLL belts could be applied to create long (>100 μm) conductive Ag@Ag nanoparticle superstructures and polymetallic, multifunctional Fe₃O₄@Ag nanoparticle composites that marry the magnetic and conductive properties of the two nanoparticle types.     

Amorphous Silica Nanoparticles Promote Monocyte Adhesion to Human Endothelial Cells: Size‐Dependent Effect

There is evidence that nanoparticles can induce endothelial dysfunction. Here, the effect of monodisperse amorphous silica nanoparticles (SiO₂‐NPs) of different diameters on endothelial cells function is examined. Human endothelial cell line (EA.hy926) or primary human pulmonary artery endothelial cells (hPAEC) are seeded in inserts introduced or not above triple cell co‐cultures (pneumocytes, macrophages, and mast cells). Endothelial cells are incubated with SiO₂‐NPs at non‐cytotoxic concentrations for 12 h. A significant increase (up to 2‐fold) in human monocytes adhesion to endothelial cells is observed for 18 and 54 nm particles. Exposure to SiO₂‐NPs induces protein expression of adhesion molecules (ICAM‐1 and VCAM‐1) as well as significant up‐regulation in mRNA expression of ICAM‐1 in both endothelial cell types. Experiments performed with fluorescent‐labelled monodisperse amorphous SiO₂‐NPs of similar size evidence nanoparticle uptake into the cytoplasm of endothelial cells. It is concluded that exposure of human endothelial cells to amorphous silica nanoparticles enhances their adhesive properties. This process is modified by the size of the nanoparticle and the presence of other co‐cultured cells.     

Enhanced Magnetism in Highly Ordered Magnetite Nanoparticle‐Filled Nanohole Arrays

A new approach to develop highly ordered magnetite (Fe₃O₄) nanoparticle‐patterned nanohole arrays with desirable magnetic properties for a variety of technological applications is presented. In this work, the sub‐100 nm nanohole arrays are successfully fabricated from a pre‐ceramic polymer mold using spin‐on nanoprinting (SNAP). These nanoholes a then filled with monodispersed, spherical Fe₃O₄ nanoparticles of about 10 nm diameter using a novel magnetic drag and drop procedure. The nanohole arrays filled with magnetic nanoparticles a imaged using magnetic force microscopy (MFM). Magnetometry and MFM measurements reveal room temperature ferromagnetism in the Fe₃O₄‐filled nanohole arrays, while the as‐synthesized Fe₃O₄ nanoparticles exhibit superparamagnetic behavior. As revealed by MFM measurements, the enhanced magnetism in the Fe₃O₄‐filled nanohole arrays originates mainly from the enhanced magnetic dipole interactions of Fe₃O₄ nanoparticles within the nanoholes and between adjacent nanoholes. Nanoparticle filled nanohole arrays can be highly beneficial in magnetic data storage and other applications such as microwave devices and biosensor arrays that require tunable and anisotropic magnetic properties.     

Efficacy Dependence of Photodynamic Therapy Mediated by Upconversion Nanoparticles: Subcellular Positioning and Irradiation Productivity

Singlet oxygen (¹O₂), as an important kind of reactive oxygen species (ROS) and main therapeutic agent in photodynamic therapy (PDT), only have a half‐life of 40 ns and an effective radius of 20 nm, which cause significant obstacles for improving PDT efficacy. In this work, novel upconversion nanoparticle (UCN)‐based nanoplatforms are developed with a minimized distance between UCNs and a photosensitizer, protoporphyrin IX (PpIX), and a controllable payload of PpIX, to enhance and control ROS production. The ability of the nanoplatform to target different subcellular organelles such as cell membrane and mitochondria is demonstrated via surface modification of the nanoplatform with different targeting ligands. The results show that the mitochondria‐targeting nanoplatforms result in significantly increased capability of both tumor cell killing and inhibition of tumor growth. Subcellular targeting of nanoparticles leads to the death of cancer cells in different manners. However, the efficiency of ROS generation almost have no influence on the tumor cell viability during the period of evaluation. These findings suggest that specific subcellular targeting of the nanoplatforms enhances the PDT efficacy more effectively than the increase of ROS production, and may shed light on future novel designs of effective and controllable PDT nanoplatforms.     

Low‐density Polyethylene Films Loaded by Titanium Dioxide and Zinc Oxide Nanoparticles as a New Active Packaging System against Escherichia coli O157:H7 in Fresh Calf Minced Meat

Antibacterial packaging is introduced as a new method to prevent microbial food spoilage. Antibacterial effects of TiO₂, ZnO and mixed TiO₂–ZnO nanoparticle‐coated low‐density polyethylene (LDPE) films on Escherichia coli PTCC1330 were investigated. Bactericidal efficiency of 0.5%, 1% and 2% TiO₂ and ZnO nanoparticles and also 1% mixed TiO₂–ZnO nanoparticles with ratios of 25/75, 50/50 and 75/25 were tested under ultraviolet (UV) and fluorescent lights at two states: films alone and fresh calf minced meat packed. Maximum colony‐forming unit (CFU) reduction of 99.8% and 99.7% were obtained using 1% and 2% ZnO nanoparticle‐coated LDPE film under fluorescent light for films alone as well as 99.8% and 99.6% for fresh calf minced meat packed. 90.3% and 51.8% CFU reduction were recorded for 1% TiO₂ nanoparticle‐coated LDPE films in the presence of UV light at direct contact with bacteria and fresh calf minced meat packed, respectively. Maximum CFU reductions of 96% and 64.1% were obtained using 50/50 ratio of TiO₂/ZnO nanoparticles at the presence of UV light for film alone and fresh calf minced meat packed, respectively. ZnO nanoparticle‐coated LDPE films were identified as the best case to improve shelf life and prevent E. coli growth in fresh calf minced meat.     

Perovskite Nanoparticle Composite Films by Size Exclusion Lithography

Perovskite nanoparticle composite films with capability of high‐resolution patterning (≥2 µm) and excellent resistance to various aqueous and organic solvents are prepared by in situ photosynthesis of acrylate polymers and formamidinium lead halide (FAPbX₃) nanoparticles. Both positive‐ and negative‐tone patterns of FAPbX₃ nanoparticles are created by controlling the size exclusive flow of nanoparticles in polymer networks. The position of nanoparticles is spatially controlled in both lateral and vertical directions. The composite films show high photoluminescence quantum yield (up to 44%) and broad color tunability in visible region (λ_peak = 465–630 nm).     

Tracking the Fate of Porous Silicon Nanoparticles Delivering a Peptide Payload by Intrinsic Photoluminescence Lifetime

A nanoparticle system for systemic delivery of therapeutics is described, which incorporates a means of tracking the fate of the nanocarrier and its residual drug payload in vivo by photoluminescence (PL). Porous silicon nanoparticles (PSiNPs) containing the proapoptotic antimicrobial peptide payload, _D[KLAKLAK]₂, are monitored by measurement of the intrinsic PL intensity and the PL lifetime of the nanoparticles. The PL lifetime of the PSiNPs is on the order of microseconds, substantially longer than the nanosecond lifetimes typically exhibited by conventional fluorescent tags or by autofluorescence from cells and tissues; thus, emission from the nanoparticles is readily discerned in the time‐resolved PL spectrum. It is found that the luminescence lifetime of the PSiNP host decreases as the nanoparticle dissolves in phosphate‐buffered saline solution (37 °C), and this correlates with the extent of release of the peptide payload. The time‐resolved PL measurement allows tracking of the in vivo fate of PSiNPs injected (via tail vein) into mice. Clearance of the nanoparticles through the liver, kidneys, and lungs of the animals is observed. The luminescence lifetime of the PSiNPs decreases with increasing residence time in the mice, providing a measure of half‐life for degradation of the drug nanocarriers.     

Metal Oxide / Silica and Metal / Silica Nanocomposites from Organofunctional Single‐Source Sol‐Gel Precursors

Single‐source precursors of the type (RO)₃Si‐X‐M, where X represents a tethering organic group and M a metal‐containing unit (metal ion or metal alkoxide group), allow the preparation of MO_x/SiO₂ or M/SiO₂ nanocomposites with a controllable nanoparticle size. After sol‐gel processing, the organic groups are removed by controlled thermal treatment, whereby the metal oxide nanoparticles are formed. This approach is exemplified for precursors based on amino‐substituted (for the late transition metals) and β‐diketonate‐substituted alkoxysilanes (for the early transition metals).     

Non-lithographic SERS substrates: tailoring surface chemistry for Au nanoparticle cluster assembly

Near‐field plasmonic coupling and local field enhancement in metal nanoarchitectures, such as arrangements of nanoparticle clusters, have application in many technologies from medical diagnostics, solar cells, to sensors. Although nanoparticle‐based cluster assemblies have exhibited signal enhancements in surface‐enhanced Raman scattering (SERS) sensors, it is challenging to achieve high reproducibility in SERS response using low‐cost fabrication methods. Here an innovative method is developed for fabricating self‐organized clusters of metal nanoparticles on diblock copolymer thin films as SERS‐active structures. Monodisperse, colloidal gold nanoparticles are attached via a crosslinking reaction on self‐organized chemically functionalized poly(methyl methacrylate) domains on polystyrene‐block‐poly(methyl methacrylate) templates. Thereby nanoparticle clusters with sub‐10‐nanometer interparticle spacing are achieved. Varying the molar concentration of functional chemical groups and crosslinking agent during the assembly process is found to affect the agglomeration of Au nanoparticles into clusters. Samples with a high surface coverage of nanoparticle cluster assemblies yield relative enhancement factors on the order of 10⁹ while simultaneously producing uniform signal enhancements in point‐to‐point measurements across each sample. High enhancement factors are associated with the narrow gap between nanoparticles assembled in clusters in full‐wave electromagnetic simulations. Reusability for small‐molecule detection is also demonstrated. Thus it is shown that the combination of high signal enhancement and reproducibility is achievable using a completely non‐lithographic fabrication process, thereby producing SERS substrates having high performance at low cost.     

Modular Integration of Upconverting Nanocrystal–Dendrimer Composites for Folate Receptor‐Specific NIR Imaging and Light‐Triggered Drug Release

Upconversion nanocrystals (UCNs) display near‐infrared (NIR)‐responsive photoluminescent properties for NIR imaging and drug delivery. The development of effective strategies for UCN integration with other complementary nanostructures for targeting and drug conjugation is highly desirable. This study reports on a core/shell‐based theranostic system designed by UCN integration with a folate (FA)‐conjugated dendrimer for tumor targeting and with photocaged doxorubicin as a cytotoxic agent. Two types of UCNs (NaYF₄:Yb/Er (or Yb/Tm); diameter = ≈50 to 54 nm) are described, each displaying distinct emission properties upon NIR (980 nm) excitation. The UCNs are surface modified through covalent attachment of photocaged doxorubicin (ONB‐Dox) and a multivalent FA‐conjugated polyamidoamine (PAMAM) dendrimer G5(FA)₆ to prepare UCN@(ONB‐Dox)(G5FA). Surface plasmon resonance experiments performed with G5(FA)₆ dendrimer alone show nanomolar binding avidity (K_D = 5.9 × 10⁻⁹m ) to the folate binding protein. This dendrimer binding corresponds with selective binding and uptake of UCN@(ONB‐Dox)(G5FA) by FAR‐positive KB carcinoma cells in vitro. Furthermore, UCN@(ONB‐Dox)(G5FA) treatment of FAR(+) KB cells inhibits cell growth in a light dependent manner. These results validate the utility of modularly integrated UCN‐dendrimer nanocomposites for cell type specific NIR imaging and light‐controlled drug release, thus serving as a new theranostic system.     

Binary Nanoparticle Superlattices for Plasmonically Modulating Upconversion Luminescence

Engineering a facile and controllable approach to modulate the spectral properties of lanthanide‐doped upconversion nanoparticles (UCNPs) is always an ongoing challenge. Herein, long‐range ordered, distinct two‐dimensional (2D) binary nanoparticle superlattices (BNSLs) composed of NaREF₄:Yb/Er (RE = Y and Gd) UCNPs and plasmonic metallic nanoparticles (Au NPs), including AB, AB₃, and AB₁₃ lattices, are fabricated via a slow evaporation‐driven self‐assembly to achieve plasmonic modulation of upconversion luminescence (UCL). Optical measurements reveal that typical red–green UCL from UCNPs can be effectively modulated into reddish output in BNSLs, with a drastically shortened lifetime. Notably, for AB₃‐ and AB₁₃‐type BNSLs with more proximal Au NPs around each UCNP, modified UCL with fine‐structured spectral lineshape is observed. These differences could be interpreted by the interplay of collective plasmon resonance introduced by 2D periodic Au arrays and spectrally selective energy transfer between UCNPs and Au. Thus, fabricating UCNP‐Au BNSLs with desired lattice parameters and NP configurations could be a promising way to tailor the UCL through controlled plasmonic modulation.     

Programmed Nanoparticle‐Loaded Nanoparticles for Deep‐Penetrating 3D Cancer Therapy

Tumors are 3D, composed of cellular agglomerations and blood vessels. Therapies involving nanoparticles utilize specific accumulations due to the leaky vascular structures. However, systemically injected nanoparticles are mostly uptaken by cells located on the surfaces of cancer tissues, lacking deep penetration into the core cancer regions. Herein, an unprecedented strategy, described as injecting “nanoparticle‐loaded nanoparticles” to address the long‐lasting problem is reported for effective surface‐to‐core drug delivery in entire 3D tumors. The “nanoparticle‐loaded nanoparticle” is a silica nanoparticle (≈150 nm) with well‐developed, interconnected channels (diameter of ≈30 nm), in which small gold nanoparticles (AuNPs) (≈15 nm) with programmable DNA are located. The nanoparticle (AuNPs)‐loaded nanoparticles (silica): (1) can accumulate in tumors through leaky vascular structures by protecting the inner therapeutic AuNPs during blood circulation, and then (2) allow diffusion of the AuNPs for penetration into the entire surface‐to‐core tumor tissues, and finally (3) release a drug triggered by cancer‐characteristic pH gradients. The hierarchical “nanoparticle‐loaded nanoparticle” can be a rational design for cancer therapies because the outer large nanoparticles are effective in blood circulation and in protection of the therapeutic nanoparticles inside, allowing the loaded small nanoparticles to penetrate deeply into 3D tumors with anticancer drugs.     

Electrostatic Self‐Assembly of Au Nanoparticles onto Thermosensitive Magnetic Core‐Shell Microgels for Thermally Tunable and Magnetically Recyclable Catalysis

A facile route to fabricate a nanocomposite of Fe₃O₄@poly[N‐isopropylacrylamide (NIPAM)‐co‐2‐(dimethylamino)ethyl methacrylate (DMAEMA)]@Au (Fe₃O₄@PND@Au) is developed for magnetically recyclable and thermally tunable catalysis. The negatively charged Au nanoparticles with an average diameter of 10 nm are homogeneously loaded onto positively charged thermoresponsive magnetic core‐shell microgels of Fe₃O₄@poly(NIPAM‐co‐DMAEMA) (Fe₃O₄@PND) through electrostatic self‐assembly. This type of attachment offers perspectives for using charged polymeric shell on a broad variety of nanoparticles to immobilize the opposite‐charged nanoparticles. The thermosensitive PND shell with swollen or collapsed properties can be as a retractable Au carrier, thereby tuning the aggregation or dispersion of Au nanoparticles, which leads to an increase or decrease of catalytic activity. Therefore, the catalytic activity of Fe₃O₄@PND@Au can be modulated by the volume transition of thermosensitive microgel shells. Importantly, the mode of tuning the aggregation or dispersion of Au nanoparticles using a thermosensitive carrier offers a novel strategy to adjust and control the catalytic activity, which is completely different with the traditional regulation mode of controlling the diffusion of reactants toward the catalytic Au core using the thermosensitive poly(N‐isopropylacrylamide) network as a nanogate. Concurrent with the thermally tunable catalysis, the magnetic susceptibility of magnetic cores enables the Fe₃O₄@PND@Au nanocomposites to be capable of serving as smart nanoreactors for thermally tunable and magnetically recyclable catalysis.     

Labeling TiO2 Nanoparticles with Dyes for Optical Fluorescence Microscopy and Determination of TiO2–DNA Nanoconjugate Stability

Visualization of nanoparticles without intrinsic optical fluorescence properties is a significant problem when performing intracellular studies. Such is the case with titanium dioxide (TiO₂) nanoparticles. These nanoparticles, when electronically linked to single‐stranded DNA oligonucleotides, have been proposed to be used both as gene knockout devices and as possible tumor imaging agents. By interacting with complementary target sequences in living cells, these photoinducible TiO₂–DNA nanoconjugates have the potential to cleave intracellular genomic DNA in a sequence specific and inducible manner. The nanoconjugates also become detectable by magnetic resonance imaging with the addition of gadolinium Gd(III) contrast agents. Herein two approaches for labeling TiO₂ nanoparticles and TiO₂–DNA nanoconjugates with optically fluorescent agents are described. This permits direct quantification of fluorescently labeled TiO₂ nanoparticle uptake in a large population of living cells (>10⁴ cells). X‐ray fluorescence microscopy (XFM) is combined with fluorescent microscopy to determine the relative intracellular stability of the nanoconjugates and used to quantify intracellular nanoparticles. Imaging the DNA component of the TiO₂–DNA nanoconjugate by fluorescent confocal microscopy within the same cell shows an overlap with the titanium signal as mapped by XFM. This strongly implies the intracellular integrity of the TiO₂–DNA nanoconjugates in malignant cells.