Photosensitizer‐Incorporated Quadruplex DNA‐Gated Nanovechicles for Light‐Triggered,Targeted Dual Drug Delivery to Cancer Cells

A novel light‐operated vehicle for targeted intracellular drug delivery is constructed using photosensitizer‐incorporated G‐quadruplex DNA‐capped mesoporous silica nanoparticles. Upon light irradiation, the photosensitizer generates ROS, causing the DNA capping to be cleaved and allowing cargo to be released. Importantly, this platform makes it possible to develop a drug‐carrier system for the synergistic combination of chemotherapy and PDT for cancer treatment with spatial/temporal control. Furthermore, the introducing of targeting ligands further improves tumor targeting efficiency. The excellent biocompatibility, cell‐specific intracellular drug delivery, and cellular uptake properties set up the basis for future biomedical application that require in vivo controlled, targeted drug delivery.     

Janus Magnetic‐Plasmonic Nanoparticles for Magnetically Guided and Thermally Activated Cancer Therapy

Progress of thermal tumor therapies and their translation into clinical practice are limited by insufficient nanoparticle concentration to release therapeutic heating at the tumor site after systemic administration. Herein, the use of Janus magneto‐plasmonic nanoparticles, made of gold nanostars and iron oxide nanospheres, as efficient therapeutic nanoheaters whose on‐site delivery can be improved by magnetic targeting, is proposed. Single and combined magneto‐ and photo‐thermal heating properties of Janus nanoparticles render them as compelling heating elements, depending on the nanoparticle dose, magnetic lobe size, and milieu conditions. In cancer cells, a much more effective effect is observed for photothermia compared to magnetic hyperthermia, while combination of the two modalities into a magneto‐photothermal treatment results in a synergistic cytotoxic effect in vitro. The high potential of the Janus nanoparticles for magnetic guiding confirms them to be excellent nanostructures for in vivo magnetically enhanced photothermal therapy, leading to efficient tumor growth inhibition.     

Super‐Resolution Microscopy Unveils Dynamic Heterogeneities in Nanoparticle Protein Corona

The adsorption of serum proteins, leading to the formation of a biomolecular corona, is a key determinant of the biological identity of nanoparticles in vivo. Therefore, gaining knowledge on the formation, composition, and temporal evolution of the corona is of utmost importance for the development of nanoparticle‐based therapies. Here, it is shown that the use of super‐resolution optical microscopy enables the imaging of the protein corona on mesoporous silica nanoparticles with single protein sensitivity. Particle‐by‐particle quantification reveals a significant heterogeneity in protein absorption under native conditions. Moreover, the diversity of the corona evolves over time depending on the surface chemistry and degradability of the particles. This paper investigates the consequences of protein adsorption for specific cell targeting by antibody‐functionalized nanoparticles providing a detailed understanding of corona‐activity relations. The methodology is widely applicable to a variety of nanostructures and complements the existing ensemble approaches for protein corona study.     

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.     

Inorganic Nanoparticles for MRI Contrast Agents

Various inorganic nanoparticles have been used as magnetic resonance imaging (MRI) contrast agents due to their unique properties, such as large surface area and efficient contrasting effect. Since the first use of superparamagnetic iron oxide (SPIO) as a liver contrast agent, nanoparticulate MRI contrast agents have attracted a lot of attention. Magnetic iron oxide nanoparticles have been extensively used as MRI contrast agents due to their ability to shorten T2* relaxation times in the liver, spleen, and bone marrow. More recently, uniform ferrite nanoparticles with high crystallinity have been successfully employed as new T2 MRI contrast agents with improved relaxation properties. Iron oxide nanoparticles functionalized with targeting agents have been used for targeted imaging via the site‐specific accumulation of nanoparticles at the targets of interest. Recently, extensive research has been conducted to develop nanoparticle‐based T1 contrast agents to overcome the drawbacks of iron oxide nanoparticle‐based negative T2 contrast agents. In this report, we summarize the recent progress in inorganic nanoparticle‐based MRI contrast agents.     

Dynamic Positron Emission Tomography Imaging of Renal Clearable Gold Nanoparticles

Optical imaging has been the primary imaging modality for nearly all of the renal clearable nanoparticles since 2007. Due to the tissue depth penetration limitation, providing accurate organ kinetics non‐invasively has long been a huge challenge. Although a more quantitative imaging technique has been developed by labeling nanoparticles with single‐photon emission computed tomography (SPECT) isotopes, the low temporal resolution of SPECT still limits its potential for visualizing the rapid dynamic process of renal clearable nanoparticles in vivo. The dynamic positron emission tomography (PET) imaging of renal clearable gold (Au) nanoparticles by labeling them with copper‐64 (⁶⁴Cu) to form ⁶⁴Cu‐NOTA‐Au‐GSH is reported. Systematic nanoparticle synthesis and characterizations are performed to demonstrate the efficient renal clearance of as‐prepared nanoparticles. A rapid renal clearance of ⁶⁴Cu‐NOTA‐Au‐GSH is observed (>75%ID at 24 h post‐injection) with its elimination half‐life calculated to be less than 6 min, over 130 times shorter than previously reported similar nanoparticles. Dynamic PET imaging not only addresses the current challenges in accurately and non‐invasively acquiring the organ kinetics, but also potentially provides a highly useful tool for studying renal clearance mechanism of other ultra‐small nanoparticles, as well as the diagnosis of kidney diseases in the near future.     

Efficient Cisplatin Pro‐Drug Delivery Visualized with Sub‐100 nm Resolution: Interfacing Engineered Thermosensitive Magnetomicelles with a Living System

Temperature‐responsive magnetic nanomicelles can serve as thermal energy and cargo carriers with controlled drug release functionality. In view of their potential biomedical applications, understanding the modes of interaction between nanomaterials and living systems and evaluation of efficiency of cargo delivery is of the utmost importance. In this work, we investigate the interaction between the hybrid magnetic nanomicelles engineered for controlled platinum complex drug delivery and a biological system at three fundamental levels: subcellular compartments, a single cell and whole living animal. Nanomicelles with polymeric P(NIPAAm‐co‐AAm)‐b‐PCL core‐shell were loaded with a hydrophobic Pt(IV) complex and Fe₃O₄ nanoparticles though self‐assembly. The distribution of a platinum complex on subcellular level is visualized using hard X‐ray fluorescence microscopy with unprecedented level of detail at sub‐100 nm spatial resolution. We then study the cytotoxic effects of platinum complex‐loaded micelles in vitro on a head and neck cancer cell culture model SQ20B. Finally, by employing the magnetic functionality of the micelles and additionally loading them with a near infrared fluorescent dye, we magnetically target them to a tumor site in a live animal xenografted model which allows to visualize their biodistribution in vivo.     

Evaluation of biotinylated magnetic nanoparticles for tumour imaging

Target-specific nanoparticles with good stability, dispersibility and targeting properties are very desirable for in vivo applications like diagnosis and therapy. In this work, the potential of covalently biotinylated magnetic nanoparticles for targeting tumours has been analysed by various in vitro and in vivo studies. For quantitatively estimating the amount of biotin bound to the surface of magnetic nanoparticles, 4-Hydroxyazobenzene-2-carboxylic acid dye was used. Varying the pH conditions changes, the mean size and zeta potential and transverse relaxivity slightly, affects the contrast enhancing capability of the synthesized biotinylated magnetic nanoparticles minimally. Cytotoxicity of the synthesized nanoconjugate was analysed in two different cell lines HeLa and A549 by using sulpho-rhodamine B assay and tumour cell-targeting capability was analysed in HeLa cell lines by using confocal microscopy. The results of cytotoxicity analysis combined with intracellular uptake, biodistribution and gamma scintigraphy prove the tumour-targeting potential of the synthesized biocompatible biotinylated magnetic nanoparticle conjugate.     

Dynamically PEGylated and Borate‐Coordination‐Polymer‐Coated Polydopamine Nanoparticles for Synergetic Tumor‐Targeted,Chemo‐Photothermal Combination Therapy

Multifunctional nanomaterials with efficient tumor‐targeting and high antitumor activity are highly anticipated in the field of cancer therapy. In this work, a synergetic tumor‐targeted, chemo‐photothermal combined therapeutic nanoplatform based on a dynamically PEGylated, borate‐coordination‐polymer‐coated polydopamine nanoparticle (PDA@CP‐PEG) is developed. PEGylation on the multifunctional nanoparticles is dynamically achieved via the reversible covalent interaction between the surface phenylboronic acid (PBA) group and a catechol‐containing poly(ethylene glycol) (PEG) molecule. Due to the acid‐labile PBA/catechol complex and the weak‐acid‐stable PBA/sialic acid (SA) complex, the nanoparticles can exhibit a synergetic targeting property for the SA‐overexpressed tumor cells, i.e., the PEG‐caused “passive targeting” and PBA‐triggered “active targeting” under the weakly acidic tumor microenvironment. In addition, the photothermal effect of the polydopamine core and the doxorubicin‐loading capacity of the porous coordination polymer layer endow the nanoparticles with the potential for chemo‐photothermal combination therapy. As expected, the in vitro and in vivo studies both verify that the multifunctional nanoparticles possess relatively lower systematic toxicity, efficient tumor targeting ability, and excellent chemo‐photothermal activity for tumor inhibition. It is believed that these multifunctional nanoparticles with synergetic tumor targeting property and combined therapeutic strategies would provide an insight into the design of a high‐efficiency antitumor nanoplatform for potential clinical applications.     

Liquid‐Phase Transmission Electron Microscopy for Studying Colloidal Inorganic Nanoparticles

For the past few decades, nanoparticles of various sizes, shapes, and compositions have been synthesized and utilized in many different applications. However, due to a lack of analytical tools that can characterize structural changes at the nanoscale level, many of their growth and transformation processes are not yet well understood. The recently developed technique of liquid‐phase transmission electron microscopy (TEM) has gained much attention as a new tool to directly observe chemical reactions that occur in solution. Due to its high spatial and temporal resolution, this technique is widely employed to reveal fundamental mechanisms of nanoparticle growth and transformation. Here, the technical developments for liquid‐phase TEM together with their application to the study of solution‐phase nanoparticle chemistry are summarized. Two types of liquid cells that can be used in the high‐vacuum conditions required by TEM are discussed, followed by recent in situ TEM studies of chemical reactions of colloidal nanoparticles. New findings on the growth mechanism, transformation, and motion of nanoparticles are subsequently discussed in detail.     

Ferritin Protein Regulates the Degradation of Iron Oxide Nanoparticles

Proteins implicated in iron homeostasis are assumed to be also involved in the cellular processing of iron oxide nanoparticles. In this work, the role of an endogenous iron storage protein—namely the ferritin—is examined in the remediation and biodegradation of magnetic iron oxide nanoparticles. Previous in vivo studies suggest the intracellular transfer of the iron ions released during the degradation of nanoparticles to endogenous protein cages within lysosomal compartments. Here, the capacity of ferritin cages to accommodate and store the degradation products of nanoparticles is investigated in vitro in the physiological acidic environment of the lysosomes. Moreover, it is questioned whether ferritin proteins can play an active role in the degradation of the nanoparticles. The magnetic, colloidal, and structural follow‐up of iron oxide nanoparticles and proteins in lysosome‐like medium confirms the efficient remediation of potentially harmful iron ions generated by nanoparticles within ferritins. The presence of ferritins, however, delays the degradation of particles due to a complex colloidal behavior of the mixture in acidic medium. This study exemplifies the important implications of intracellular proteins in processes of degradation and metabolization of iron oxide nanoparticles.     

Upconversion Nanoparticles–Based Multiplex Protein Activation to Neuron Ablation for Locomotion Regulation

The optogenetic neuron ablation approach enables noninvasive remote decoding of specific neuron function within a complex living organism in high spatiotemporal resolution. However, it suffers from shallow tissue penetration of visible light with low ablation efficiency. This study reports a upconversion nanoparticle (UCNP)–based multiplex proteins activation tool to ablate deep‐tissue neurons for locomotion modulation. By optimizing the dopant contents and nanoarchitecure, over 300‐fold enhancement of blue (450–470 nm) and red (590–610 nm) emissions from UCNPs is achieved upon 808 nm irradiation. Such emissions simultaneously activate mini singlet oxygen generator and Chrimson, leading to boosted near infrared (NIR) light–induced neuronal ablation efficiency due to the synergism between singlet oxygen generation and intracellular Ca²⁺ elevation. The loss of neurons severely inhibits reverse locomotion, revealing the instructive role of neurons in controlling motor activity. The deep penetrance NIR light makes the current system feasible for in vivo deep‐tissue neuron elimination. The results not only provide a rapidly adoptable platform to efficient photoablate single‐ and multiple‐cells, but also define the neural circuits underlying behavior, with potential for development of remote therapy in diseases.     

Mechanism for the Cellular Uptake of Targeted Gold Nanorods of Defined Aspect Ratios

Biomedical applications of non‐spherical nanoparticles such as photothermal therapy and molecular imaging require their efficient intracellular delivery, yet reported details on their interactions with the cell remain inconsistent. Here, the effects of nanoparticle geometry and receptor targeting on the cellular uptake and intracellular trafficking are systematically explored by using C166 (mouse endothelial) cells and gold nanoparticles of four different aspect ratios (ARs) from 1 to 7. When coated with poly(ethylene glycol) strands, the cellular uptake of untargeted nanoparticles monotonically decreases with AR. Next, gold nanoparticles are functionalized with DNA oligonucleotides to target Class A scavenger receptors expressed by C166 cells. Intriguingly, cellular uptake is maximized at a particular AR: shorter nanorods (AR = 2) enter C166 cells more than nanospheres (AR = 1) and longer nanorods (AR = 4 or 7). Strikingly, long targeted nanorods align to the cell membrane in a near‐parallel manner followed by rotating by ≈90° to enter the cell via a caveolae‐mediated pathway. Upon cellular entry, targeted nanorods of all ARs predominantly traffic to the late endosome without progressing to the lysosome. The studies yield important materials design rules for drug delivery carriers based on targeted, anisotropic nanoparticles.     

Single Chain Epidermal Growth Factor Receptor Antibody Conjugated Nanoparticles for in vivo Tumor Targeting and Imaging

Epidermal growth factor receptor (EGFR) targeted nanoparticle are developed by conjugating a single‐chain anti‐EGFR antibody (ScFvEGFR) to surface functionalized quantum dots (QDs) or magnetic iron oxide (IO) nanoparticles. The results show that ScFvEGFR can be successfully conjugated to the nanoparticles, resulting in compact ScFvEGFR nanoparticles that specifically bind to and are internalized by EGFR‐expressing cancer cells, thereby producing a fluorescent signal or magnetic resonance imaging (MRI) contrast. In vivo tumor targeting and uptake of the nanoparticles in human cancer cells is demonstrated after systemic delivery of ScFvEGFR‐QDs or ScFvEGFR‐IO nanoparticles into an orthotopic pancreatic cancer model. Therefore, ScFvEGFR nanoparticles have potential to be used as a molecular‐targeted in vivo tumor imaging agent. Efficient internalization of ScFvEGFR nanoparticles into tumor cells after systemic delivery suggests that the EGFR‐targeted nanoparticles can also be used for the targeted delivery of therapeutic agents.     

Observation of Fano Resonances in All‐Dielectric Nanoparticle Oligomers

It is well‐known that oligomers made of metallic nanoparticles are able to support sharp Fano resonances originating from the interference of two plasmonic resonant modes with different spectral width. While such plasmonic oligomers suffer from high dissipative losses, a new route for achieving Fano resonances in nanoparticle oligomers has opened up after the recent experimental observations of electric and magnetic resonances in low‐loss dielectric nanoparticles. Here, light scattering by all‐dielectric oligomers composed of silicon nanoparticles is studied experimentally for the first time. Pronounced Fano resonances are observed for a variety of lithographically‐fabricated heptamer nanostructures consisting of a central particle of varying size, encircled by six nanoparticles of constant size. Based on a full collective mode analysis, the origin of the observed Fano resonances is revealed as a result of interference of the optically‐induced magnetic dipole mode of the central particle with the collective mode of the nanoparticle structure. This allows for effective tuning of the Fano resonance to a desired spectral position by a controlled size variation of the central particle. Such optically‐induced magnetic Fano resonances in all‐dielectric oligomers offer new opportunities for sensing and nonlinear applications.     

Possibilities and impossibilities of magnetic nanoparticle use in the control of infectious biofilms

Targeting of chemotherapeutics towards a tumor site by magnetic nanocarriers is considered promising in tumor-control. Magnetic nanoparticles are also considered for use in infection-control as a new means to prevent antimicrobial resistance from becoming the number one cause of death by the year 2050. To this end, magnetic nanoparticles can either be loaded with an antimicrobial for use as a delivery vehicle or modified to acquire intrinsic antimicrobial properties. Magnetic nanoparticles can also be used for the local generation of heat to kill infectious microorganisms. Although appealing for tumor-and infectioncontrol, injection in the blood circulation may yield reticuloendothelial uptake and physical obstruction in organs that yield reduced targeting efficiency. This can be prevented with suitable surface modification. However, precise techniques to direct magnetic nanoparticles towards a target site are lacking. The problem of precise targeting is aggravated in infection-control due to the micrometer-size of infectious biofilms, as opposed to targeting of nanoparticles towards centimeter-sized tumors. This review aims to identify possibilities and impossibilities of magnetic targeting of nanoparticles for infection-control. We first review targeting techniques and the spatial resolution they can achieve as well as surface-chemical modifications of magnetic nanoparticles to enhance their targeting efficiency and antimicrobial efficacy.It is concluded that targeting problems encountered in tumor-control using magnetic nanoparticles, are neglected in most studies on their potential application in infection-control. Currently biofilm targeting by smart, self-adaptive and pH-responsive, antimicrobial nanocarriers for instance, seems easier to achieve than magnetic targeting. This leads to the conclusion that magnetic targeting of nanoparticles for the control of micrometer-sized infectious biofilms may be less promising than initially expected.However, using propulsion rather than precise targeting of magnetic nanoparticles in a magnetic field to traverse through infectious-biofilms can create artificial channels for enhanced antibiotic transport.This is identified as a more feasible, innovative application of magnetic nanoparticles in infection-control than precise targeting and distribution of magnetic nanoparticles over the depth of a biofilm.     

pH‐Responsive Isoniazid‐Loaded Nanoparticles Markedly Improve Tuberculosis Treatment in Mice

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.     

Two‐Photon In Vivo Imaging with Porous Silicon Nanoparticles

A major obstacle in luminescence imaging is the limited penetration of visible light into tissues and interference associated with light scattering and autofluorescence. Near‐infrared (NIR) emitters that can also be excited with NIR radiation via two‐photon processes can mitigate these factors somewhat because they operate at wavelengths of 650–1000 nm where tissues are more transparent, light scattering is less efficient, and endogenous fluorophores are less likely to absorb. This study presents photolytically stable, NIR photoluminescent, porous silicon nanoparticles with a relatively high two‐photon‐absorption cross‐section and a large emission quantum yield. Their ability to be targeted to tumor tissues in vivo using the iRGD targeting peptide is demonstrated, and the distribution of the nanoparticles with high spatial resolution is visualized.     

Amino Acid Metabolism Abnormity and Microenvironment Variation Mediated Targeting and Controlled Glioma Chemotherapy

Energy metabolism abnormity is one of the most significant hallmarks of cancer. As a result, large amino acid transporter 1 (LAT1) is remarkably overexpressed in both blood‐brain‐barrier and glioma tumor cells, leading a rapid and sufficient substrate transportation. 3CDIT and 4CDIT are originally synthesized by modifying the existing most potent LAT1 substrate. 3CDIT is selected as its higher glioma‐targeting ability. Since the microenvironment variation in tumor cells is another important feature of cancer, a great disparity in adenosine‐5′‐triphosphate (ATP) and glutathione (GSH) levels between extracellular and intracellular milieu can provide good possibilities for dual‐responsive drug release in tumor cells. Doxorubicin (DOX) is successfully intercalated into the ATP aptamer DNA scaffolds, compressed by GSH‐responsive polymer pOEI, and modified with 3CDIT to obtain 3CDIT‐targeting pOEI/DOX/ATP aptamer nanoparticles (NPs). Enhanced NP accumulation and rapid GSH & ATP dual‐responsive DOX release in glioma are demonstrated both in vitro and in vivo. More efficient therapeutic effects are shown with 3CDIT‐targeting pOEI/DOX/ATP aptamer NPs than free DOX and no systemic toxicity is observed. Therefore, glioma‐targeting delivery and GSH & ATP dual‐responsive release guarantee an adequate DOX accumulation within tumor cells and ensure a safe and efficient chemotherapy for glioma.