Self-Assembly of Selenium-Doped Carbon Quantum Dots as Antioxidants for Hepatic Ischemia-Reperfusion Injury Management

Hepatic ischemia-reperfusion injury (HIRI) is a critical complication after liver surgery that negatively affects surgical outcomes of patients with the end-stage liver-related disease. Reactive oxygen species (ROS) are responsible for the development of ischemia-reperfusion injury and eventually lead to hepatic dysfunction. Selenium-doped carbon quantum dots (Se-CQDs) with an excellent redox-responsive property can effectively scavenge ROS and protect cells from oxidation. However, the accumulation of Se-CQDs in the liver is extremely low. To address this concern, the fabrication of Se-CQDs-lecithin nanoparticles (Se-LEC NPs) is developed through self-assembly mainly driven by the noncovalent interactions. Lecithin acting as the self-assembly building block also makes a pivotal contribution to the therapeutic performance of Se-LEC NPs due to its capability to react with ROS. The fabricated Se-LEC NPs largely accumulate in the liver, effectively scavenge ROS and inhibit the release of inflammatory cytokines, thus exerting beneficial therapeutic efficacy on HIRI. This work may open a new avenue for the design of self-assembled Se-CQDs NPs for the treatment of HIRI and other ROS-related diseases.     

Mechanistic Investigation of the Biological Effects of SiO2, TiO2, and ZnO Nanoparticles on Intestinal Cells

Silicon dioxide (SiO₂), titanium dioxide (TiO₂), and zinc oxide (ZnO) are currently among the most widely used nanoparticles (NPs) in the food industry. This could potentially lead to unintended exposure of the gastrointestinal tract to these NPs. This study aims to investigate the potential side‐effects of these food‐borne NPs on intestinal cells and to mechanistically understand the observed biological responses. Among the panel of tested NPs, ZnO NPs are the most toxic. Consistently in all three tested intestinal cell models, ZnO NPs invoke the most inflammatory responses from the cells and induce the highest intracellular production of reactive oxygen species (ROS). The elevated ROS levels induce significant damage to the DNA of the cells, resulting in cell‐cycle arrest and subsequently cell death. In contrast, both SiO₂ and TiO₂ NPs elicit minimum biological responses from the intestinal cells. Overall, the study showcases the varying capability of the food‐borne NPs to induce a cellular response in the intestinal cells. In addition to physicochemical differences in the NPs, the genetic landscape of the intestinal cell models governs the toxicology profile of these food‐borne NPs.     

A Mussel‐Inspired Persistent ROS‐Scavenging,Electroactive, and Osteoinductive Scaffold Based on Electrochemical‐Driven In Situ Nanoassembly

Conductive polymers are promising for bone regeneration because they can regulate cell behavior through electrical stimulation; moreover, they are antioxidative agents that can be used to protect cells and tissues from damage originating from reactive oxygen species (ROS). However, conductive polymers lack affinity to cells and osteoinductivity, which limits their application in tissue engineering. Herein, an electroactive, cell affinitive, persistent ROS‐scavenging, and osteoinductive porous Ti scaffold is prepared by the on‐surface in situ assembly of a polypyrrole‐polydopamine‐hydroxyapatite (PPy‐PDA‐HA) film through a layer‐by‐layer pulse electrodeposition (LBL‐PED) method. During LBL‐PED, the PPy‐PDA nanoparticles (NPs) and HA NPs are in situ synthesized and uniformly coated on a porous scaffold from inside to outside. PDA is entangled with and doped into PPy to enhance the ROS scavenging rate of the scaffold and realize repeatable, efficient ROS scavenging over a long period of time. HA and electrical stimulation synergistically promote osteogenic cell differentiation on PPy‐PDA‐HA films. Ultimately, the PPy‐PDA‐HA porous scaffold provides excellent bone regeneration through the synergistic effects of electroactivity, cell affinity, and antioxidative activity of the PPy‐PDA NPs and the osteoinductivity of HA NPs. This study provides a new strategy for functionalizing porous scaffolds that show great promise as implants for tissue regeneration.     

Dual pH/ROS‐Responsive Nanoplatform with Deep Tumor Penetration and Self‐Amplified Drug Release for Enhancing Tumor Chemotherapeutic Efficacy

Poor deep tumor penetration and incomplete intracellular drug release remain challenges for antitumor nanomedicine application in clinical settings. Herein, a nanomedicine (RLPA‐NPs) is developed that can achieve prolonged blood circulation, deep tumor penetration, active‐targeting of cancer cells, endosome/lysosome escape, and intracellular selectivity self‐amplified drug release for effective drug delivery. The RLPA‐NPs are constructed by encapsulation of a pH‐sensitive polymer octadecylamine‐poly(aspartate‐1‐(3‐aminopropyl) imidazole) (OA‐P(Asp‐API)) and a ROS‐generation agent, β‐Lapachone (Lap), in micelles assembled by the tumor‐penetration peptide internalizing RGD (iRGD)‐modified ROS‐responsive paclitaxel (PTX)‐prodrug. iRGD could promote RLPA‐NPs penetration into deep tumor tissue, and specific targeting to cancer cells. After internalization by cancer cells through receptor‐mediated endocytosis, OA‐P(Asp‐API) can rapidly protonate in the endosome's acidic environment, resulting in RLPA‐NPs escape from the endosome through the “proton sponge effect”. At the same time, the RLPA‐NPs micelle disassembles, releasing Lap and PTX‐prodrug. Subsequently, the released Lap could generate ROS, consequently amplifying and accelerating PTX release to kill tumor cells. The in vitro and in vivo studies demonstrated that RLPA‐NPs can significantly improve the therapeutic effect compared to control groups. Therefore, RLPA‐NPs are a promising nanoplatform for overcoming multiple physiological and pathological barriers to enhance drug delivery.     

Functionalization of Carbon Nanoparticles Modulates Inflammatory Cell Recruitment and NLRP3 Inflammasome Activation

The inflammatory effects of carbon nanoparticles (NPs) are highly disputed. Here it is demonstrated that endotoxin‐free preparations of raw carbon nanotubes (CNTs) are very limited in their capacity to promote inflammatory responses in vitro, as well as in vivo. Upon purification and selective oxidation of raw CNTs, a higher dispersibility is achieved in physiological solutions, but this process also enhances their inflammatory activity. In synergy with toll‐like receptor (TLR) ligands, CNTs promote NLRP3 inflammasome activation and it is shown for the first time that this property extends to spherical carbon nano‐onions (CNOs) of 6 nm in size. In contrast, the benzoic acid functionalization of purified CNTs and CNOs leads to significantly attenuated inflammatory properties. This is evidenced by a reduced secretion of the inflammatory cytokine IL‐1β, and a pronounced decrease in the recruitment of neutrophils and monocytes following injection into mice. Collectively, these results reveal that the inflammatory properties of carbon NPs are highly dependent on their physicochemical characteristics and crucially, that chemical surface functionalization allows significant moderation of these properties.     

Adipose‐Derived Biogenic Nanoparticles for Suppression of Inflammation

Extracellular vesicles secreted from adipose‐derived mesenchymal stem cells (ADSCs) have therapeutic effects in inflammatory diseases. However, production of extracellular vesicles (EVs) from ADSCs is costly, inefficient, and time consuming. The anti‐inflammatory properties of adipose tissue‐derived EVs and other biogenic nanoparticles have not been explored. In this study, biogenic nanoparticles are obtained directly from lipoaspirate, an easily accessible and abundant source of biological material. Compared to ADSC‐EVs, lipoaspirate nanoparticles (Lipo‐NPs) take less time to process (hours compared to months) and cost less to produce (clinical‐grade cell culture facilities are not required). The physicochemical characteristics and anti‐inflammatory properties of Lipo‐NPs are evaluated and compared to those of patient‐matched ADSC‐EVs. Moreover, guanabenz loading in Lipo‐NPs is evaluated for enhanced anti‐inflammatory effects. Apolipoprotein E and glycerolipids are enriched in Lipo‐NPs compared to ADSC‐EVs. Additionally, the uptake of Lipo‐NPs in hepatocytes and macrophages is higher. Lipo‐NPs and ADSC‐EVs have comparable protective and anti‐inflammatory effects. Specifically, Lipo‐NPs reduce toll‐like receptor 4‐induced secretion of inflammatory cytokines in macrophages. Guanabenz‐loaded Lipo‐NPs further suppress inflammatory pathways, suggesting that this combination therapy can have promising applications for inflammatory diseases.     

Foodborne Titanium Dioxide Nanoparticles Induce Stronger Adverse Effects in Obese Mice than Non‐Obese Mice: Gut Microbiota Dysbiosis,Colonic Inflammation,and Proteome Alterations

The recent ban of titanium dioxide (TiO₂) as a food additive (E171) in France intensified the controversy on safety of foodborne‐TiO₂ nanoparticles (NPs). This study determines the biological effects of TiO₂ NPs and TiO₂ (E171) in obese and non‐obese mice. Oral consumption (0.1 wt% in diet for 8 weeks) of TiO₂ (E171, 112 nm) and TiO₂ NPs (33 nm) does not cause severe toxicity in mice, but significantly alters composition of gut microbiota, for example, increased abundance of Firmicutes phylum and decreased abundance of Bacteroidetes phylum and Bifidobacterium and Lactobacillus genera, which are accompanied by decreased cecal levels of short‐chain fatty acids. Both TiO₂ (E171) and TiO₂ NPs increase abundance of pro‐inflammatory immune cells and cytokines in the colonic mucosa, indicating an inflammatory state. Importantly, TiO₂ NPs cause stronger colonic inflammation than TiO₂ (E171), and obese mice are more susceptible to the effects. A microbiota transplant study demonstrates that altered fecal microbiota by TiO₂ NPs directly mediate inflammatory responses in the mouse colon. Furthermore, proteomic analysis shows that TiO₂ NPs cause more alterations in multiple pathways in the liver and colon of obese mice than non‐obese mice. This study provides important information on the health effects of foodborne inorganic nanoparticles.     

Hepatic histopathological and ultrastructural alterations induced by 10 nm silver nanoparticles

Silver nanoparticles (Ag NPs) are invested in various sectors and are becoming more persistent in our ambient environment with potential risk on our health and the ecosystems. The current study aims to investigate the histological, histochemical and ultrastructural hepatic changes that might be induced by 10 nm silver nanomaterials. Male mice (BALB/C) were exposed for 35 injections of daily dose of 10 nm Ag NPs (2 mg/kg). Liver tissues were subjected to examination by light and electron microscopy for histological, histochemical and ultrastructural alterations. Exposure to Ag NPs induced Kupffer cells hyperplasia, sinusoidal dilatation, apoptosis, ground glass hepatocytes appearance, nuclear changes, inflammatory cells infiltration, hepatocytes degeneration and necrosis. In addition, 10 nm Ag NPs induced histochemical alterations mainly glycogen depletion with no hemosiderin precipitation. Moreover, these nanomaterials exhibited ultrastructure alterations including mitochondrial swelling and cristolysis, cytoplasmic vacuolation, apoptosis, multilammellar myelin figures formation and endoplasmic destruction and reduction. The findings revealed that Ag NPs can induce alterations in the hepatic tissues, the chemical components of the hepatocytes and in the ultrastructure of the liver. One may also conclude that small size Ag NPs, which are increasingly used in human products could cause various toxigenic responses to all hepatic tissue components.Inspec keywords: liver, electron microscopy, molecular biophysics, optical microscopy, toxicology, biochemistry, silver, biological tissues, nanofabrication, cellular biophysics, biomedical materials, nanoparticles, nanomedicineOther keywords: hepatic histopathological alterations, ultrastructural alterations, silver nanoparticles, histological changes, histochemical changes, ultrastructural hepatic changes, silver nanomaterials, male mice, liver tissues, electron microscopy, histological alterations, histochemical alterations, Kupffer cells hyperplasia, sinusoidal dilatation, apoptosis, ground glass hepatocytes appearance, inflammatory cells infiltration, hepatocyte degeneration, necrosis, ultrastructure alterations, Ag, size 10.0 nm, hepatic tissue components, cytoplasmic vacuolation     

ROS‐Responsive Polyprodrug Nanoparticles for Triggered Drug Delivery and Effective Cancer Therapy

The application of nanoparticles (NPs) to drug delivery has led to the development of novel nanotherapeutics for the treatment of various diseases including cancer. However, clinical use of NP‐mediated drug delivery has not always translated into improved survival of cancer patients, in part due to the suboptimal properties of NP platforms, such as premature drug leakage during preparation, storage, or blood circulation, lack of active targeting to tumor tissue and cells, and poor tissue penetration. Herein, an innovative reactive oxygen species (ROS)‐responsive polyprodrug is reported that can self‐assemble into stable NPs with high drug loading. This new NP platform is composed of the following key components: (i) polyprodrug inner core that can respond to ROS for triggered release of intact therapeutic molecules, (ii) polyethylene glycol (PEG) outer shell to prolong blood circulation; and (iii) surface‐encoded internalizing RGD (iRGD) to enhance tumor targeting and tissue penetration. These targeted ROS‐responsive polyprodrug NPs show significant inhibition of tumor cell growth both in vitro and in vivo.     

Mechanistic Differences in Cell Death Responses to Metal‐Based Engineered Nanomaterials in Kupffer Cells and Hepatocytes

The mononuclear phagocyte system in the liver is a frequent target for nanoparticles (NPs). A toxicological profiling of metal‐based NPs is performed in Kupffer cell (KC) and hepatocyte cell lines. Sixteen NPs are provided by the Nanomaterial Health Implications Research Consortium of the National Institute of Environmental Health Sciences to study the toxicological effects in KUP5 (KC) and Hepa 1–6 cells. Five NPs (Ag, CuO, ZnO, SiO₂, and V₂O₅) exhibit cytotoxicity in both cell types, while SiO₂ and V₂O₅ induce IL‐1β production in KC. Ag, CuO, and ZnO induced caspase 3 generated apoptosis in both cell types is accompanied by ion shedding and generation of mitochondrial reactive oxygen species (ROS) in both cell types. However, the cell death response to SiO₂ in KC differs by inducing pyroptosis as a result of potassium efflux, caspase 1 activation, NLRP3 inflammasome assembly, IL‐1β release, and cleavage of gasdermin‐D. This releases pore‐performing peptide fragments responsible for pyroptotic cell swelling. Interestingly, although V₂O₅ induces IL‐1β release and delays caspase 1 activation by vanadium ion interference in membrane Na⁺/K⁺ adenosine triphosphate (ATP)ase activity, the major cell death mechanism in KC (and Hepa 1–6) is caspase 3 mediated apoptosis. These findings improve the understanding of the mechanisms of metal‐based engineered nanomaterial (ENM) toxicity in liver cells toward comprehensive safety evaluation.     

Free‐Blockage Mesoporous Anticancer Nanoparticles Based on ROS‐Responsive Wetting Behavior of Nanopores

To achieve an excellent delivery effect of drug, stimuli‐responsive nano “gate” with physical blockage units is usually constructed on the surface of the mesoporous silica nanocarriers (MSNs). In nature, the aquaporins in cell membrane can control the transport of water molecules by regulating the channel wettability, which is resulted from the conformational change of amino acids in the channel. Inspired by this phonomenon, herein a new concept of free‐blockage controlled release system is proposed, which is achieved by controlling the wettability of the internal surface of nanopores on MSNs. Such a new system is different from the physical‐blockage controlled release system, which bypasses the use of nano “gate” and overcomes the limitations of traditional physical blockage system. Moreover, further studies have shown that the system can selectively release the entrapped doxorubicin in human breast adenocarcinoma (MCF‐7) cells triggered by intracellular reactive oxygen species (ROS) but not in normalhuman umbilical vein endothelial cells (HUVECs) containing ROS with low levels. The wettability‐determined free‐blockage controlled release system is simple and effective, and it can also be triggered by intracellular biological stimuli, which provides a new approach for the future practical application of drug delivery and cancer therapy.     

Spatiotemporal Catalytic Nanozymes Microneedle Patches with Opposite Properties for Wound Management

Reactive oxygen species (ROS)-mediated biological catalysis involves serial programmed enzymatic reactions and plays an important part against infectious diseases; while the spatiotemporal control of catalytic treatment to break the limitations of the disease microenvironment is challenging. Here, a novel spatiotemporal catalytic microneedles patch (CMSP-MNs) integrated with dual-effective Cu₂MoS₄ (CMS) and polydopamine (PDA) nanoparticles (NPs) for breaking microenvironment restrictions to treat wound infections is designed. Since CMS NPs are loaded in the needles, CMSP-MNs can catalytically generate diverse ROS to cause effective bacterial inactivation during bacterial infection process. Besides, PDA NPs are encapsulated in the backing layer, which facilitate ROS elimination and oxygen production for solving hypoxic problems in wound microenvironment and alleviating the expression of inflammatory factors during the inflammation process. Based on these features, it is demonstrated through cell and animal experiments that these nanozymes-integrated MNs patches can realize selective regulation of ROS level with bacterial inactivation and inflammatory treatment, resulting in minimized side effects of over-production ROS and effective anti-infected treatment. It is believed that the presented MNs can provide a new therapeutic strategy with spatiotemporal adjustable catalytic properties in biomedical areas.     

Multiphoton Microscopy of Nonfluorescent Nanoparticles In Vitro and In Vivo

Nanotechnology holds great promise for a plethora of potential applications. The interaction of engineered nanomaterials with living cells, tissues, and organisms is, however, only partly understood. Microscopic investigations of nano‐bio interactions are mostly performed with a few model nanoparticles (NPs) which are easy to visualize, such as fluorescent quantum dots. Here the possibility to visualize nonfluorescent NPs with multiphoton excitation is investigated. Signals from silver (Ag), titanium dioxide (TiO₂), and silica (SiO₂) NPs in nonbiological environments are characterized to determine signal dependency on excitation wavelength and intensity as well as their signal stability over time. Ag NPs generate plasmon‐induced luminescence decaying over time. TiO₂ NPs induce photoluminescent signals of variable intensities and in addition strong third harmonic generation (THG). Optimal settings for microscopic detection are determined and then applied for visualization of these two particle types in living cells, in murine muscle tissue, and in the murine blood stream. Silica NPs produce a THG signal, but in living cells it cannot be discriminated sufficiently from endogenous cellular structures. It is concluded that multiphoton excitation is a viable option for studies of nano‐bio interactions not only for fluorescent but also for some types of nonfluorescent NPs.     

Physicochemical and Biological Properties of Biomimetic Mineralo‐Protein Nanoparticles Formed Spontaneously in Biological Fluids

Recent studies indicate that mineral nanoparticles (NPs) form spontaneously in human body fluids. These biological NPs represent mineral precursors that are associated with ectopic calcifications seen in various human diseases. However, the parameters that control the formation of mineral NPs and their possible effects on human cells remain poorly understood. Here a nanomaterial approach to study the formation of biomimetic calcium phosphate NPs comparable to their physiological counterparts is described. Particle sizing using dynamic light scattering reveals that serum and ion concentrations within the physiological range yield NPs below 100 nm in diameter. While the particles are phagocytosed by macrophages in a size‐independent manner, only large particles or NP aggregates in the micrometer range induce cellular responses that include production of mitochondrial reactive oxygen species, caspase‐1 activation, and secretion of interleukin‐1β (IL‐1β). A comprehensive proteomic analysis reveals that the particle‐bound proteins are similar in terms of their identity and number, regardless of particle size, suggesting that protein adsorption is independent of particle size and curvature. In conclusion, the conditions underlying the formation of mineralo‐protein particles are similar to the ones that form in vivo. While mineral NPs do not activate immune cells, they may become pro‐inflammatory and contribute to pathological processes once they aggregate and form larger mineral particles.     

Cyclodextrin‐Derived Intrinsically Bioactive Nanoparticles for Treatment of Acute and Chronic Inflammatory Diseases

Inflammation is a common cause of many acute and chronic inflammatory diseases. A major limitation of existing anti‐inflammatory therapeutics is that they cannot simultaneously regulate pro‐inflammatory cytokine production, oxidative stress, and recruitment of neutrophils and macrophages. To overcome this limitation, nanoparticles (NPs) with multiple pharmacological activities are synthesized, using a chemically modified cyclic oligosaccharide. The manufacture of this type of bioactive, saccharide material‐based NPs (defined as LCD NP) is straightforward, cost‐effective, and scalable. Functionally, LCD NP effectively inhibits inflammatory response, oxidative stress, and cell migration for both neutrophils and macrophages, two major players of inflammation. Therapeutically, LCD NP shows desirable efficacies for the treatment of acute and chronic inflammatory diseases in mouse models of peritonitis, acute lung injury, and atherosclerosis. Mechanistically, the therapeutic benefits of LCD NP are achieved by inhibiting neutrophil‐mediated inflammatory macrophage recruitment and by preventing subsequent pro‐inflammatory events. In addition, LCD NP shows good safety profile in a mouse model. Thus, LCD NP can serve as an effective anti‐inflammatory nanotherapy for the treatment of inflammatory diseases mainly associated with neutrophil and macrophage infiltration.     

Stimulus‐Responsive Anti‐Oxidizing Drug Crystals and their Ecological Implication

Various antioxidants are being used to neutralize the harmful effects of reactive oxygen species (ROS) overproduced in diseased tissues and contaminated environments. Polymer‐directed crystallization of antioxidants has attracted attention as a way to control drug efficacy through molecular dissolution. However, most recrystallized antioxidants undertake continuous dissolution independent of the ROS level, thus causing side‐effects. This study demonstrates a unique method to assemble antioxidant crystals that modulate their dissolution rate in response to the ROS level. We hypothesized that antioxidants recrystallized using a ROS‐labile polymer would be triggered to dissolve when the ROS level increases. We examined this hypothesis by using catechin as a model antioxidant. Catechin was recrystallized using polyethylenimine cross‐linked with ROS‐labile diselanediylbis‐(ethane‐2,1‐diyl)‐diacrylate. Catechin crystallized with the ROS‐labile polymer displays accelerated dissolution proportional to the H₂O₂ concentration. The ROS‐responsive catechin crystals protect vascular cells from oxidative insults by activating intracellular glutathione peroxidase expression and, in turn, inhibiting an increase in the intracellular oxidative stress. In addition, ROS‐responsive catechin crystals alleviate changes in the heart rate of Daphnia magna in oxidative media. We propose that the results of this study would be broadly useful for improving the therapeutic efficacy of a broad array of drug compounds.     

Corannulene‐Incorporated AIE Nanodots with Highly Suppressed Nonradiative Decay for Boosted Cancer Phototheranostics In Vivo

Fluorescent nanoparticles (NPs) based on luminogens with aggregation‐induced emission characteristic (AIEgens), namely AIE dots, have received wide attention because of their antiquenching attitude in emission and reactive oxygen species (ROS) generation when aggregated. However, few reports are available on how to control and optimize their fluorescence and ROS generation ability. Herein, it is reported that enhancing the intraparticle confined microenvironment is an effective approach to advanced AIE dots, permitting boosted cancer phototheranostics in vivo. Formulation of a “rotor‐rich” and inherently charged near‐infrared (NIR) AIEgen with 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐N‐[methoxy(polyethylene glycol)‐2000] and corannulene‐decorated PEG affords DSPE‐AIE dots and Cor‐AIE dots, respectively. Compared to DSPE‐AIE dots, Cor‐AIE dots show 4.0‐fold amplified fluorescence quantum yield and 5.4‐fold enhanced ROS production, because corannulene provides intraparticle rigidity and strong interactions with the AIEgen to restrict the intramolecular rotation of AIEgen to strongly suppress the nonradiative decay and significantly facilitate the fluorescence pathway and intersystem crossing. Thus, it tremendously promotes phototheranostic efficacies in terms of NIR image‐guided cancer surgery and photodynamic therapy using a peritoneal carcinomatosis‐bearing mouse model. Collectively, it not only provides a novel strategy to advanced AIE dots for cancer phototheranostics, but also brings new insights into the design of superior fluorescent NPs for biomedical applications.     

Cytotoxicity of titanium dioxide nanoparticles differs in four liver cells from human and rat

Titanium dioxide (TiO₂) nanoparticles (NPs) are the important nanoscale components of composites. Although TiO₂ NPs and their related nanocomposites have been widely used in industrial and medical applications, the adverse effects of TiO₂ nanomaterials have not been well studied. Here, we investigated the cytotoxicity of TiO₂ NPs in vitro using four liver cell lines: human hepatocellular carcinoma cell line (SMMC-7721), human liver cell line (HL-7702), rat hepatocarcinoma cell line (CBRH-7919) and rat liver cell line (BRL-3A). We checked cell viability, cell morphology, and the levels of reactive oxygen species (ROS) and glutathione (GSH) after TiO₂ exposure at varying concentrations (0.1–100 μg/mL) and different exposure periods of time (12–48 h). Compared to the NP-free control, all four cell lines exposed to TiO₂ NPs showed cytotoxicity in a dosage-dependent and time-dependent manner, which was associated with the changes of cell viability and cell morphology, increased intercellular ROS levels, and decreased intracellular GSH levels. Further, we observed that carcinomatous liver cells and human liver cells exhibited more tolerance to TiO₂ NPs exposure for 24 h, compared to normal liver cells and rat liver cells, respectively. The results indicate that the in vitro cytotoxicity induced by NPs should be assessed with great caution before the use of nanocomposites and that there is a need to standardize the cytotoxicity testing procedure of nanoscale components in composites when using different cell lines.     

Dye‐Anchored MnO Nanoparticles Targeting Tumor and Inducing Enhanced Phototherapy Effect via Mitochondria‐Mediated Pathway

Phototherapy is a promising treatment method for cancer therapy. However, the various factors have greatly restricted phototherapy development, including the poor accumulation of photosensitizer in tumor, hypoxia in solid tumor tissue and systemic phototoxicity. Herein, a mitochondrial‐targeted multifunctional dye‐anchored manganese oxide nanoparticle (IR808@MnO NP) is developed for enhancing phototherapy of cancer. In this nanoplatform, IR808 as a small molecule dye acts as a tumor targeting ligand to make IR808@MnO NPs with capacity to actively target tumor cells and relocate finally in the mitochondria. Meanwhile, continuous production of oxygen (O₂) and regulation of pH induced by the high reactivity and specificity of MnO NPs toward mitochondrial endogenous hydrogen peroxide (H₂O₂) could effectively modulate tumor hypoxia and lessen the tumor subacid environment. Large amounts of reactive oxide species (ROS) are generated during the reaction process between H₂O₂ and MnO NPs. Furthermore, under laser irradiation, IR808 in IR808@MnO NPs turns O₂ into a highly toxic singlet oxygen (¹O₂) and generates hyperthermia. The results indicate that IR808@MnO NPs have the high efficiency of specific targeting of tumors, relieving tumor subacid environment, improving the tumor hypoxia environment, and generating large amounts of ROS to kill tumor cells. It is expected to have a wide application in treating cancer.     

Tuning Cellular Response to Nanoparticles via Surface Chemistry and Aggregation

The aggregation of gold nanoparticles (Au NPs) in cell media is a common phenomenon that can influence NP‐cell interactions. Here, we control Au NP aggregation in cell media and study the impact of Au NP aggregation on human dermal fibroblast (HDF) cells. By first adding Au NPs to fetal bovine serum (FBS) and then subsequently to a buffer, aggregation can be avoided. Aggregation of Au NPs also can be avoided by coating Au NPs with other biomolecules such as lipids. The aggregation state of the Au NPs influences cellular toxicity and Au NP uptake: non‐aggregated cationic Au NPs are four‐fold less toxic to HDF cells than aggregated cationic Au NPs, and the uptake of non‐aggregated anionic citrate Au NPs is three orders of magnitude less than that of aggregated citrate Au NPs. Upon uptake of Au NPs, cellular F‐actin fiber formation is disrupted and actin dots are predominant. When lipid‐coated Au NPs are doped with a fluorescent lipid (F‐lipid) and incubated with HDF cells, the fluorescence from the F‐lipid was found throughout the cell, showing that lipids can dissociate from the Au NP surface upon entering the cell.