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The development of antibiotic-loaded microneedles has been hindered for years by limited excipient options, restricted drug-loading space, poor microneedle formability, and short-term drug retention. Therefore, this study proposes a dissolving microneedle fabricated from the host-defense peptide ε-poly-l-lysine (EPL) as an antibacterial adjuvant system for delivering antibiotics. EPL serves not only as a major matrix material for the microneedle tips, but also as a broad-spectrum antibacterial agent that facilitates the intracellular accumulation of the antibiotic doxycycline (DOX) by increasing bacterial cell membrane permeability. Furthermore, the formation of physically crosslinked networks of EPL affords microneedle tips with improved formability, good mechanical properties, and amorphous nanoparticles (approximately 7.2 nm) of encapsulated DOX. As a result, a high total loading content of both antimicrobials up to 2319.1 μg/patch is achieved for efficient transdermal drug delivery. In a Pseudomonas aeruginosa-induced deep cutaneous infection model, the EPL microneedles demonstrates potent and long-term effects by synergistically enhancing antibiotic activities and prolonging drug retention in infected lesions, resulting in remarkable therapeutic efficacy with 99.91 % (3.04 log) reduction in skin bacterial burden after a single administration. Overall, our study highlights the distinct advantages of EPL microneedles and their potential in clinical antibacterial practice when loaded with amorphous DOX nanoparticles., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Elesclomol (ES), a copper-binding ionophore, forms an ES-Cu complex with copper ions (Cu(II)). ES-Cu has been proven to induce mitochondrial oxidative stress and copper-dependent cell death (cuprotosis). However, ES-Cu is poorly water-soluble, and its delivery to various cancer cells is a challenge. Herein, we designed a d-α-tocopherol polyethylene glycol 1000 succinate/chondroitin sulfate-cholic acid (TPGS/CS-CA)-based micellar nanoparticle for delivering the ES-Cu complex to various cancer cell lines to demonstrate its efficacy as an anticancer agent. The ES-Cu nanoparticles exerted high encapsulation efficiency and excellent serum stability. The anticancer efficacy of ES-Cu nanoparticles was evaluated in various drug-sensitive cell lines (DU145, PC3, and A549) and drug-resistant cell lines (DU145TXR, PC3TXR, and A549TXR). The results showed that ES-Cu nanoparticles exerted potent anticancer activities in both drug-sensitive and drug-resistant cell lines. The Western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and molecular docking results suggested that ES-Cu is not a substrate for P glycoprotein (P-gp), which is an efflux transporter potentially causing multidrug resistance (MDR) in cancer cells. ES-Cu nanoparticles could bypass P-gp without compromising their activity, indicating that they may overcome MDR in cancer cells and provide a novel therapeutic strategy. Additionally, the extracellular matrix of ES-Cu nanoparticles-pretreated drug-resistant cells could polarize Raw 264.7 macrophages into the M1 phenotype. Therefore, our TPGS/CS-CA-based ES-Cu nanoparticles provide an effective method of delivering the ES-Cu complex, a promising strategy to overcome MDR in cancer therapy with potential immune response stimulation.

A vital challenge is to develop water-stable perovskite nanocrystals owing to the easy attack of its surface vacancy defects by water-molecule. Here, a facile surface-passivated strategy to dramatically improve the chem-stability and luminescent efficiency (LE) of the CsPbBr 3 nanocrystals (CPB) is proposed, where sodium dodecyl sulfate (SDS) encapsulate on CPB, generating confined environment (named SDS@CPB). The flexible long carbon-chain of SDS can confine the movement of CPB to form an externally hydrophobic closed-shell and internally structural rigidity through the hydrophobic association between surface hydrophobic groups, improving the LE and maintaining long-term composition of CPB. While the sulfate group in SDS can reduce the surface-defects exposure of CPB through the coordination with Pb 2+ , inhibiting the invasion of water-molecule. Importantly, an SDS@CPB-based sensor was fabricated to detect amaranth in food samples with a lower detection limit (5.43 nM), which opens a new avenue for food sensing based on high-efficiency perovskite nanocrystals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Protein nanocages (PNCs) hold great promise for developing multifunctional nanomedicines. Long blood circulation is a key requirement of PNCs for most in vivo application scenarios. In addition to the classical PEGylation strategy, short peptides with a specific sequence screened via phage display are also very effective in prolonging the blood half-life (t 1/2 ) of PNCs. However, there is a lack of knowledge on how individual amino acids affect the circulation of PNCs. Here the effects of the 20 proteinogenic amino acids in the form of an X 3 or X 5 tag (X represents an amino acid) are explored on the pharmacokinetics of PNCs, which lead to the formation of a heatmap illustrating the extent of t 1/2 prolongation by each proteinogenic amino acid. Significantly, oligo-lysine and oligo-arginine can effectively prolong the t 1/2 of strongly negatively charged PNCs through charge neutralization, while oligo-cysteine can also do so, but via a different mechanism, mediating the covalent binding of PNCs with plasma albumin as a stealth material. These findings are extendible and offer guidance for surface-engineering biosynthetic PNCs and other nanoparticles., (© 2023 Wiley-VCH GmbH.)

Fatty acid photodecarboxylase in Chlorella variabilis NC64A (CvFAP) performed excellent ability to exclusively decarboxylate renewable fatty acids for C1-shortened hydrocarbons fuel production under visible light. However, the large-scale application by such an approach is limited by the free state of CvFAP catalyst, which is unstable for efficient biofuel production. In this study, CvFAP was immobilized in magnetic nickel ferrite (NiFe 2 O 4 ) nanoparticles for facile recovery by a simple procedure. The shift of Ni 2p in electron binding energy was detected to clarify the interaction between Ni 2+ and histidine of CvFAP. The coordination of NiFe 2 O 4 and CvFAP contributed to an efficient affinity binding with an immobilization capacity of 98 mg/g carrier. Hydrocarbon fuel concentration of 3.7 mM was obtained by NiFe 2 O 4 @CvFAP-induced photoenzymatic decarboxylation. The high stability of CvFAP in terms of residual enzyme activity of 79.7% at pH 9.0 and that of 68% at organic solvent ratio of 60%, respectively, were observed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Abnormal expression of hydrogen peroxide (H 2 O 2 ) elucidates cell dysfunctions and might induce the occurrence and deterioration of various diseases. However, limited by its ultralow level under pathophysiological conditions, intracellular and extracellular H 2 O 2 was difficult to be detected accurately. Herein, a colorimetric and homogeneous electrochemical dual-mode biosensing platform was constructed for intracellular/extracellular H 2 O 2 detection based on FeS x /SiO 2 nanoparticles (FeS x /SiO 2 NPs) with high peroxidase-like activity. In this design, FeS x /SiO 2 NPs were synthesized with excellent catalytic activity and stability compared to natural enzymes, which improved the sensitivity and stability of sensing strategy. 3,3',5,5'-Tetramethylbenzidine (TMB), as a multifunctional indicator, was oxidized in the presence of H 2 O 2 , generated color changes and realized visual analysis. In this process, the characteristic peak current of TMB decreased, which could realize the ultrasensitive detection of H 2 O 2 by homogeneous electrochemistry. Accordingly, by integrating visual analysis ability of colorimetry and the high sensitivity of homogeneous electrochemistry, the dual-mode biosensing platform exhibited high accuracy, sensitivity and reliability. The detection limits of H 2 O 2 were 0.2 μM (S/N = 3) for the colorimetric method and 2.5 nM (S/N = 3) for the homogeneous electrochemistry assay. Therefore, the dual-mode biosensing platform provided a new opportunity for highly accurate and sensitive detection of intracellular/extracellular H 2 O 2 ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Laser-induced Fe 3 O 4 nanoparticle-modified three-dimensional macroporous graphene is fabricated as a near-infrared light responsive nanozyme via a facile and in situ laser-scanning method under ambient conditions for the first time, showing an excellent catalytic-photothermal synergetic bactericidal ability under a low dose of H 2 O 2 (0.1 mM) and short irradiation time (5.0 min).

Proanthocyanidins (Pas) are widely used in the preparation of functional foods due to their diverse biological activities. Taking advantage of the effect of Pas on the stability of Pickering emulsions, this study constructed the zein-proanthocyanidins-pectin ternary composites (ZPAAPs) as stabilizer to establish Pickering emulsions with potential delivery capacity. The appearance of the emulsion was pink which could be found in visual observation. The emulsion was stable during long-term storage in the range of 0.1 ∼ 0.7 oil phase. CLSM showed that the oil droplets were coated with covering layer formed by ZPAAPs, which effectively prevented droplets congregating. The rheological results indicated that ZPAAPEs had elastic gel-like structure. In addition, ZPAAPEs still contained 54.4 % curcumin after storage for 15 d. And the bioavailability of curcumin was increased to 39.7 % ± 0.3. These studies may contribute to the controllable fabrication of Pickering emulsions for nutrient delivery in the food and pharmaceutical fields., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Due to the small size, high mobility and large surface area, nanoplastics (NPs) showed high potential risks to aquatic organisms. This paper reviews the toxicity of NPs to aquatic organism at various trophic levels including bacteria, plankton (algae), zooplankton, benthos, and nekton (fish). The effects at individual level caused by NPs were explained and proved by cytotoxicity and genotoxicity, and the toxicity of NPs beyond individual level was also illustrated. The toxicity of NPs is determined by the size, dosage, and surface property of NPs, as well as environmental factors, the presence of co-contaminants and the sensitivity of tested organisms. Furthermore, the joint effects of NPs with other commonly detected pollutants such as organic pollutants, metals, and nanoparticles etc. were summarized. In order to reflect the toxicity of NPs in the real natural environment, studies on toxicity assessment of NPs with the coexistence of various environmental factors and contaminants, particularly under the concentrations in natural environment are suggested., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Glioblastoma multiforme (GBM) is an aggressive brain cancer with a poor prognosis and few treatment options. Here, building on the observation of elevated lactate (LA) in resected GBM, we develop biomimetic therapeutic nanoparticles (NPs) that deliver agents for LA metabolism-based synergistic therapy. Because our self-assembling NPs are encapsulated in membranes derived from glioma cells, they readily penetrate the blood-brain barrier and target GBM through homotypic recognition. After reaching the tumors, lactate oxidase in the NPs converts LA into pyruvic acid (PA) and hydrogen peroxide (H 2 O 2 ). The PA inhibits cancer cell growth by blocking histones expression and inducing cell-cycle arrest. In parallel, the H 2 O 2 reacts with the delivered bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate to release energy, which is used by the co-delivered photosensitizer chlorin e6 for the generation of cytotoxic singlet oxygen to kill glioma cells. Such a synergism ensures strong therapeutic effects against both glioma cell-line derived and patient-derived xenograft models., (© 2022. The Author(s).)

The effects of emerging contaminants micro/nanoplastics (MPs/NPs) and silver nanoparticles (Ag NPs) on health have attracted universal concern throughout the world. However, it is unclear on the combined effects of MPs/NPs and Ag NPs on the biogeochemistry cycle such as nitrogen transformation and functional microorganism in the soil. In the present study, we conducted a 45-day soil microcosm experiment with polystyrene (PS) MPs/NPs and Ag NPs to investigate their combined impact on nitrogen cycling and the bacterial community. The results showed that MPs or NPs exerted limited effects on nitrogen transformation in the soil. The combined effects of PS MPs/NPs and Ag NPs were mainly caused by the presence of Ag NPs. However, PS NPs alleviated the inhibition of anammox and denitrification induced by Ag NPs via upregulating anammox-related genes and elevating nitrate and nitrite reductase activities. PS MPs + Ag NPs treatment significantly reduced bacterial diversity. PS MPs/NPs + Ag NPs increased the relative abundances of denitrifying Cupriavidus by 0.32% and 0.06% but decreased nitrogen-fixing functional microorganisms of Microvirga (by 2.05% and 2.24%), Bacillus (by 0.16% and 0.22%), and Herbaspirillum (by 0.14% and 0.07%) at the genus level compared with Ag NPs alone. The significant downregulation of nitrogen-fixing genes (K02586, K02588, and K02591) was observed in PS MPs/NPs + Ag NPs treatment compared to Ag NPs in the nitrogen metabolism pathway. Moreover, g-Lysobacter and g-Aquimonas were identified as biomarkers in PS MPs + Ag NPs and PS NPs + Ag NPs by LEfSe analysis. Our study sheds the light that changes of functional microorganism abundances contributed to the alteration of nitrogen transformation. Taking the particle size of plastics into account will be helpful to accurately assess the combined ecological risks of plastics and nanomaterial contaminants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Photodynamic therapy (PDT) is a therapeutic strategy that is dependent on external light irradiation that faces a major challenge in cancer treatment due to the poor tissue-penetration depths of light irradiation. Herein, a DNA nanocomplex that integrates persistent-luminescence nanoparticles (PLNPs) is developed, which realizes tumor-site glutathione-activated PDT for breast cancer without exogenous laser excitation. The scaffold of the nanocomplex is AS1411-aptamer-encoded ultralong single-stranded DNA chain with two functions: i) providing sufficient intercalation sites for the photosensitizer, and ii) recognizing nucleolin that specifically overexpresses on the surface of cancer cells. The PLNPs in the nanocomplex are energy-charged to act as a self-illuminant and coated with a shell of MnO 2 for blocking energy degradation. In response to the overexpressed glutathione in cancer cells, the MnO 2 shell decomposes to provide Mn 2+ to catalytically produce O 2 , which is essential to PDT. Meanwhile, PLNPs are released and act as a self-illuminant to activate the photosensitizer to convert O 2 into cytotoxic 1 O 2 . Significant tumor inhibition effects are demonstrated in breast tumor xenograft models without exogenous laser excitation. It is envisioned that a laser-excitation-free PDT strategy enabled by the PLNP-DNA nanocomplex promotes the development of PDT and provides a new local therapeutic approach., (© 2022 Wiley-VCH GmbH.)

Ferritin (Fn) is considered a promising carrier for targeted delivery to tumors, but the successful application in vivo has not been fully achieved yet. Herein, strong evidence is provided that the Fn receptor is expressed in liver tissues, resulting in an intercept effect in regards to tumor delivery. Building on these observations, a biomineralization technology is rationally designed to shield Fn using a calcium phosphate (CaP) shell, which can improve the delivery performance by reducing Fn interception in the liver while re-exposing it in acidic tumors. Moreover, the selective dissolution of the CaP shell not only neutralizes the acidic microenvironment but also induces the intratumoral immunomodulation and calcification. Upon multiple cell line and patient-derived xenografts, it is demonstrated that the elaboration of the highly flexible Fn@CaP chassis by loading a chemotherapeutic drug into the Fn cavity confers potent antitumor effects, and additionally encapsulating a photosensitizer into the outer shell enables a combined chemo-photothermal therapy for complete suppression of advanced tumors. Altogether, these results support Fn@CaP as a new nanoplatform for efficient modulation of the tumor microenvironment and targeted delivery of diverse therapeutic agents., (© 2021 Wiley-VCH GmbH.)

Hyperoside (HYP) has various potential benefits, however, its low water-solubility and poor bioavailability have restricted its application. Here, HYP-loaded zein-tea polyphenols (TP)-pectin ternary complex nanoparticles (Z/TP/P-HYP) were prepared by the antisolvent precipitation method for HYP delivery. The formed Z/TP/P-HYP are negatively charged spherical particles with a size of 246 nm, and have the highest HYP encapsulation efficiency (94.2%) at TP was 0.25 mg/mL. Fourier transform infrared spectroscopy revealed that hydrogen bonding, electrostatic interactions, and hydrophobic effects were major interactions to Z/TP/P-HYP formation. Differential scanning calorimetry confirmed that encapsulated HYP was in an amorphous state. Freeze-dried Z/TP/P-HYP displayed good water-redispersibility and high particle yield (95.2%). Z/TP/P-HYP exhibited improved pH (2.0-8.0) and ionic (0-500 mM) stability. Furthermore, Z/TP/P-HYP demonstrated stronger antioxidant properties than free HYP and provided HYP sustained release under simulated gastrointestinal conditions. Therefore, Z/TP/P-HYP have great potential as an effective HYP delivery system for applications in foods., (Copyright © 2021. Published by Elsevier Ltd.)

Incorporating multiple molecular interactions within a system to realize the metabolic reprogramming of cancer cells is prospected to be of great potential in cancer therapy. Herein, we report a supramolecular self-assembled DNA nanosystem, which reprogrammed the cellular antioxidant system via synergistic chemical and gene regulations. In the nanosystem, amphipathic telluroether was coordinated with Mn II to self-assemble into micelle, on which a siNrf2 integrated DNA network was assembled. The great electron-donating capability of telluroether was revealed to greatly promote Mn II -based Fenton-like reaction to generate subversive . OH in cancer cells. In response to adenosine triphosphoric acid, the siNrf2 was specially released in cytoplasm for down-regulating expression of detoxification enzymes, which enhanced chemocatalysis-mediated oxidative stress in cancer cells, thus significantly suppressing tumor progression., (© 2021 Wiley-VCH GmbH.)

Disulfiram copper complex [Cu(DDC) 2 ] nanoparticles have been explored as promising anticancer agents but with concerns of toxic side effects. To improve tumor specificity and enhance anticancer efficacy, we developed a novel [copper sulfide nanoparticle (CuS NP) + disulfiram prodrug (DQ) micelle + near-infrared (NIR) laser] (CDL) combination therapy. DQ, a reactive oxygen species (ROS)-responsive prodrug, can be selectively activated at the tumor site with elevated ROS to release DDC and form Cu(DDC) 2 in situ. The CuS NP + NIR laser treatment can effectively increase the intra-tumor ROS levels and efficiently activate the DQ prodrug. The CDL therapy kills cancer cells through multiple mechanisms, including ROS amplification cascade and Cu(DDC) 2 chemotherapy. NIR light-triggered tumor-specific "nontoxic-to-toxic" transition can significantly improve the specificity of anticancer effects and reduce systemic toxicity. Also, CDL therapy can effectively induce immunogenic cell death (ICD) and has the potential of eliciting antitumor immunity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Anticancer nanomedicines are designed to improve anticancer efficacy by increasing drug accumulation in tumors through enhanced permeability retention (EPR) effect, and to reduce toxicity by decreasing drug accumulation in normal organs through long systemic circulation. However, the inconsistent efficacy/safety of nanomedicines in cancer patients versus preclinical cancer models have provoked debate for nanomedicine design criteria. In this study, we investigate nanomedicine design criteria in three types of preclinical cancer models using five clinically used nanomedicines, which identifies the factors for better clinical translations of their observed clinical efficacy/safety compared to free drug or clinical micelle formulation. When those nanomedicines were compared with drug solution or clinical micelle formulation in breast tumors, long and short-circulating nanomedicines did not enhance tumor accumulation by EPR effect in transgenic spontaneous breast cancer model regardless of their size or composition, although they improved tumor accumulations in subcutaneous and orthotopic breast cancer models. However, when tumors were compared to normal breast tissue, nanomedicines, drug solution and clinical micelle formulation showed enhanced tumor accumulation regardless of the breast cancer models. In addition, long-circulating nanomedicines did not further increase tumor accumulation in transgenic mouse spontaneous breast cancer nor universally decrease drug accumulations in normal organs; they decreased or increased accumulation in different organs, potentially changing the clinical efficacy/safety. In contrast, short-circulating nanomedicines decreased blood concentration and altered drug distribution in normal organs, which are correlated with their clinical efficacy/safety. A reappraisal of current nanomedicine design criteria is needed to ensure consistent clinical translation for improvement of their clinical efficacy/safety in cancer patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Osimertinib (OSI) is the first FDA-approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It can be used for treating non-small cell lung cancer (NSCLC) patients with activating EGFR mutation and for patients who are resistant to first-generation EGFR TKIs due to T790M resistance mutation. However, patients treated with OSI ultimately develop acquired resistance, which prevents its long-term benefit for patients. Therefore, the development of effective strategies to overcome OSI resistance will address a significant clinical challenge and benefit patients by prolonging their survival time. Our previous studies indicated that combination therapy was a promising strategy for overcoming OSI resistance. In this study, we developed nanoparticle (NP) formulations for co-delivery of osimertinib (OSI) and selumetinib (SEL) to treat OSI-resistant NSCLC effectively. We conjugated SEL with PEG through a reactive oxygen species (ROS)-responsive linker to generate polyethylene glycol (PEG)-SEL conjugate prodrug (PEG-S-SEL). Due to the amphiphilic nature of PEG-S-SEL, it can self-assemble in an aqueous solution to form micelle NP and serve as a delivery carrier for OSI. The ROS-responsive linker can facilitate the release of drugs in the tumor microenvironment with elevated ROS levels. OSI and SEL combination NP can overcome OSI resistance by simultaneously inhibiting both EGFR and mitogen-activated protein kinase (MEK), thus effectively inducing apoptosis in OSI-resistant NSCLC cells and inhibiting OSI-resistant tumors in vivo. In conclusion, the OSI+SEL NP combination therapy showed promising anticancer efficacy and demonstrated potential for treating NSCLC patients with OSI acquired resistance. STATEMENT OF SIGNIFICANCE: Osimertinib (OSI) is the first FDA-approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. It has been successfully used for treating non-small cell lung cancer (NSCLC) patients with activating EGFR mutation. However, patients treated with OSI ultimately develop acquired resistance. This study developed OSI and selumetinib (SEL) co-delivering nanoparticles to overcome OSI-acquired resistance in NSCLC. PEG-SEL conjugate functions as reactive oxygen species (ROS)-responsive prodrug and forms micelle nanoparticles through self-assembly to deliver OSI. The combination NP can simultaneously inhibit EGFR and mitogen-activated protein kinase (MEK), thus effectively inducing apoptosis in OSI-resistant NSCLC cells. In summary, the OSI and SEL nanoparticle combination therapy showed promising anticancer efficacy and demonstrated potential for treating NSCLC patients with OSI acquired resistance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Tumor targeting with nanoparticles is a promising strategy for cancer diagnosis and treatment, especially for drug delivery to solid tumors. Previous studies mainly focused on nanoparticle design to improve their targeting efficiency, but few have investigated the impact of tumor progression stages on the targeting efficiency. Here, we used PEGylated viral nanoparticles (VNPs) of bacteriophage P22 to explore the relationship between targeting efficiency and tumor progression stages using a colorectal cancer model. We found an 8.1-fold increase in the accumulation of P22 VNPs systematically injected 7 days after tumor inoculation compared with those injected 21 days after tumor inoculation. Most tumor-targeted P22 VNPs were concentrated in tumor-associated macrophages in the tumor blood vessels, the density of which decreased with the progression of tumors. These results reveal that the tumor targeting efficiency of P22 VNPs decreased with tumor progression. These findings provide valuable information for not only the understanding of controversial observations regarding targeted cancer therapy in experimental and clinical studies but also the design of nanoparticle-based tumor targeting probes or therapeutics.

Cancer remains a significant challenge despite the progress in developing different therapeutic approaches. Nanomedicine has been explored as a promising novel cancer therapy. Recently, biomimetic camouflage strategies have been investigated to change the bio-fate of therapeutics and target cancer cells while reducing the unwanted exposure on normal tissues. Endogenous components (e.g., proteins, polysaccharides, and cell membranes) have been used to develop anticancer drug delivery systems. These biomimetic systems can overcome biological barriers and enhance tumor cell-specific uptake. The tumor-targeting mechanisms include ligand-receptor interactions and stimuli-responsive (e.g., pH-sensitive and light-sensitive) delivery. Drug delivery carriers composed of endogenous components represent a promising approach for improving cancer treatment efficacy. In this paper, different biomimetic drug delivery strategies for cancer treatment are reviewed with a focus on the discussion of their advantages and potential applications.

The use of carbon-based nanomaterials as effective photocatalysts is an ideal alternative for environmental remediation. Here, (3-aminopropyl)triethoxysilane-functionalized carbon nanoparticles (SiCNPs) were prepared using a simple pyrolysis method with sodium citrate and urea as the precursors. The samples were characterized by X-ray diffraction, transmission electron microscopy, ultraviolet-visible diffuse reflectance spectroscopy, X-ray photoelectron spectroscopy, photoluminescence spectroscopy, and photo-electrochemical measures. The obtained SiCNPs-2.0 showed a better visible light response and more effective photocatalytic activity for degradation of methylene blue (MB) compared with pure CNPs. Under visible light irradiation, 98.8% of the MB was decomposed within 75 min when SiCNPs-2.0 was used as the photocatalyst. The high photocatalytic activities of SiCNPs-2.0 could be attributed to enhanced light absorption in the visible region, and improved photogenerated electron-hole separation efficiency. A possible photocatalytic mechanism for removal of MB over SiCNPs-2.0 was proposed based on active species trapping experiments. Recycling experiments showed that SiCNPs-2.0 had good stability during photocatalysis. This work provides a new easy method to synthesize carbon-based nanomaterials and to catalytically degrade organic pollutants in water under visible light irradiation., (© 2020 John Wiley & Sons, Ltd.)

The development of organic nanoparticles that fluoresce in the near-infrared, especially in the second near-infrared (NIR-II) window, improves in vivo fluorescence imaging due to deeper penetration and higher spatiotemporal resolution. We report two kinds of NIR-II fluorescent molecules with twisted intramolecular charge-transfer (TICT) and aggregation-induced emission (AIE) characteristics. The virus-like particles (VLPs) of simian virus 40 (SV40) were used as templates to encapsulate the molecules in a well-defined structure (referred to as CH1-SV40 and CH2-SV40). The CH1-SV40 dots exhibited a highly uniform size of 21.5 nm, strong fluorescence, high photostability, and good biocompatibility in vitro and in vivo. Their fluorescence spectrum exhibited a peak at 955 nm, with a tail extending to 1200 nm. Moreover, the CH1-SV40 dots, with a quantum yield of 13.03%, enabled blood vessel imaging and image-guided surgery with a high signal-to-background ratio. Overall, the hybrid nanoparticles represent a new kind of NIR-II AIE nanoprobes for biomedical imaging.

Background: Colon cancer is a top lethal cancer in man and women worldwide and drug resistance is the major cause of cancer-related death. Combinational therapy and drug delivery with nanoparticles have been shown to effectively overcome drug resistance in many cancers. We previously reported that nanoemulsion (NE) loaded paclitaxel (PTX) and BEZ235 could synergistically inhibit colon cancer cell growth., Purpose: To investigate whether NE loaded PTX and BEZ235 can overcome drug resistance and synergistically inhibit drug-resistant colon cancer cell growth in vitro and in vivo., Methods: The in vitro treatment effect on cell viability was assayed using CCK8 kit, cell morphological change was detected by β-tubulin immunofluorescence staining, drug resistance-related proteins were analyzed by Western blotting, and in vivo tumor growth test was performed in nude mice xeno-transplanted with 2 drug-resistant colon cancer cell lines HCT116-LOHP and HT29-DDP., Results: Both cell lines were sensitive to PTX but relatively insensitive to BEZ235. PTX combined with BEZ235 synergistically inhibited the proliferation of both cell lines. Nanoemulsion loaded PTX (NE-PTX) reduced the IC50 of PTX to approximately 2/5 of free PTX, indicating a high inhibitory efficacy of NE-PTX. When NE-PTX combined with a low concentration of BEZ235 (50 nM), the IC50 was decreased to approximately 2/3 of free PTX. Moreover, NE-PTX+BEZ235 treatment increased apoptosis, decreased Pgp and ABCC1 expression, and reduced tumor weights compared to the single drug treatment and the control group. These results suggest that nanoemulsion loaded PTX+BEZ235 can overcome drug resistance and improve the inhibitory effect on cancer cell proliferation and tumor growth., Conclusion: Our study thus provides a possible new approach to treat colon cancer patients with drug resistance., Competing Interests: Yali Hu, Kunpeng Zhang, and Xingyao Zhu are co-first authors for this study. The authors declare no conflicts of interest., (© 2021 Hu et al.)

We report the first demonstration using a stable π-radical as a versatile photosensitizer for hypoxia-overcoming photodynamic therapy. After self-assembling the radical molecules into radical nanoparticles (NPs), the NPs show good water dispersibility, good biocompatibility, broad near-infrared (NIR) absorption and emission at ∼800 nm. Significantly, the radical NPs remain stable in various biological mediums, after 100 days exposure to the ambient environment, and even after long-term laser irradiation, which is superior to many reported radical-based materials. More importantly, upon 635 nm laser irradiation, sufficient superoxide radical (O 2 - ˙) generation and in vitro cytotoxicity were observed addressing the most important hurdle for successful PDT in the oxygen-deficient tumor microenvironment. In addition, the radical NPs are also demonstrated to have effective in vivo PDT efficacy, and excellent biosafety.

Luminescence nanothermometry is promising for noninvasive probing of temperature in biological microenvironment at nanometric spatial resolution. Yet, wavelength- and temperature-dependent absorption and scattering of tissues distort measured spectral profile, rendering conventional luminescence nanothermometers (ratiometric, intensity, band shape, or spectral shift) problematic for in vivo temperature determination. Here, a class of lanthanide-based nanothermometers, which are able to provide precise and reliable temperature readouts at varied tissue depths through NIR-II luminescence lifetime, are described. To achieve this, an inert core/active shell/inert shell structure of tiny nanoparticles (size, 13.5 nm) is devised, in which thermosensitive lanthanide pairs (ytterbium and neodymium) are spatially confined in the thin middle shell (sodium yttrium fluoride, 1 nm), ensuring being homogenously close to the surrounding environment while protected by the outmost calcium fluoride shell (CaF 2 , ≈2.5 nm) that shields out bioactive milieu interferences. This ternary structure enables the nanothermometers to consistently resolve temperature changes at depths of up to 4 mm in biological tissues, having a high relative temperature sensitivity of 1.4-1.1% °C -1 in the physiological temperature range of 10-64 °C. These lifetime-based thermosensitive nanoprobes allow for in vivo diagnosis of murine inflammation, mapping out the precise temperature distribution profile of nanoprobes-interrogated area., (© 2020 Wiley-VCH GmbH.)

As the combination of photothermal therapy (PTT) with immunotherapy provides an effective strategy in cancer treatment, a magnetic nanoparticle delivery system was constructed to load indocyanine green (ICG) and immunostimulator R837 hydrochloride (R837) for spatio-temporally PTT/immunotherapy synergism in cancer. This delivery system is composed of Fe 3 O 4 magnetic nanoparticles (MPs) as the core to load ICG and polyethylene glycol polyphenols (DPA-PEG) as the coating layer to load R837, which formed R837 loaded polyphenols coating ICG loaded magnetic nanoparticles (MIRDs). After intravenous injection, the formed MIRDs resulted in long circulation, magnetic resonance imaging (MRI) guides, and magnetic targeting. Once targeting to the tumor, the MIRDs with the near-infrared (NIR) irradiation caused tumor ablation and resulted in tumor-associated antigens releasing to induce the body's immunological response, which was markedly improved it to attack the tumors with the R837 releasing from the outer DPA-PEG. In this case, the synergism of the PTT and immunotherapy inhibited tumor growth, metastasis and recurrence, which resulted in potent anticancer therapeutic effects with few side effect., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Triple-negative breast cancer (TNBC) has a high rate of metastasis, which is associated with breast cancer stem-like cells (CSCs). Although Taxol (micelle formulation of paclitaxel) is the first line chemotherapy to treat TNBC, it increases CSCs in residual tumors. Abraxane, albumin nanoparticle of paclitaxel, showed lower plasma concentration compared to Taxol in both human and animal models, but it is not clear why Abraxane showed superior efficacy to Taxol in treatment of metastatic breast cancer in humans. In this study, we intend to investigate if Abraxane eliminates CSCs for its better efficacy. The results showed that Abraxane showed similar cytotoxicity in SUM149 cells in comparison with Taxol. Although Abraxane showed 3- to 5-fold lower blood drug concentration compared to Taxol, it achieved similar tumor drug concentration and 10-fold higher tumor/plasma ratio in SUM149 xenograft NOD/SCID mouse model. In addition, Abraxane and Taxol showed similar efficacy to shrink the tumor size in orthotopic breast cancer NOD/SCID mouse model. However, Abraxane decreased breast CSCs frequency by 3- to 9-fold, while Taxol increased breast CSCs frequency in an orthotopic breast cancer NOD/SCID mouse model. Furthermore, Abraxane increased 3- to 15-fold intracellular uptake in both ALDH+ CSCs and differentiated ALDH- cells in comparison with Taxol, which provides a mechanism for Abraxane's superior efficacy to eliminate CSCs in comparison with Taxol. Our data suggest albumin nanoparticle Abraxane may have a broad implication to enhance drug's efficacy by eliminating breast cancer stem cells for treatment of metastatic diseases.

We developed a competitive coordination-based immobilization-free electrochemical biosensor for highly sensitive and selective detection of arsenic(v) using a CeO 2 -DNA nanoprobe, which effectively circumvented complicated modification procedures and successfully achieved arsenic(v) determination in natural water samples.

Recently, the use of emulsion as a delivery system for essential oils has attracted increasing attention. In this research, cinnamon essential oil Pickering emulsion (ZCCPEs) stabilized by zein-pectin composite nanoparticles (ZCPs) was constructed as an effective antimicrobial system. Thereafter, the influence of ZCPs concentration on the stability of ZCCPEs was studied. The results showed that 0.25% ZCPs could reduce the bioorganic matter by four times compared with 1% ZCPs while maintaining good physical stability. The inhibitory effect of ZCCPEs on two food-related microorganisms (i.e. Alternaria alternata and Botrytis cinerea) was evaluated by antimicrobial assay. In addition, two fresh-cut apple slices models were constructed to systematically evaluate the application potential of ZCCPEs in food preservation. Due to the well dispersibility and sustained-release ability, ZCCPEs showed superior antibacterial performance than pure essential oil. The fabricated zein-pectin based Pickering emulsions might provide a promising alternative for the delivery of antimicrobial essential oils in the food industries., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Colloidal nanoparticle biosensors capable of on-particle biocatalysis are powerful tools for amplified detection of biomolecules. The development and practical uses of such concentric amplifiers can be complicated because of the on-particle biorecognition that involves varying interfacial factors at the biomolecule-nanoparticle interfaces. Herein, we reason that a nanoparticle biosensor equipped with an in-solution biorecognition element may be better fabricated, predicted, controlled, and performed. The in-solution biorecognition shall also be streamlined with the on-particle biocatalysis so that the overall analytical and kinetic performance is not compromised. As a testbed, we introduce a concentric DNA amplifier driven by an enzyme-powered three-dimensional DNA nanomachine, where a DNA walker can be instantly assembled onto a spherical nucleic acid (SNA) track through a polyadenosine anchor. As such, the free DNA walker can participate in reactions in a homogeneous solution before assembling to the SNA track. The instant and stable assembly enabled by both adsorption and complementary base pairing also ensures rapid on-particle biocatalysis. We demonstrate that the in-solution biorecognition effectively eliminates the binding hindrance encountered by the on-particle biorecognition and thus significantly reduced energy barriers for the detection of nucleic acids and proteins. Because of the in-solution biorecognition, our system can also be plugged readily into complex DNA strand displacement networks for rapid signal amplification.

Metastasis is the primary cause of cancer morbidity and mortality. To obtain an effective diagnosis and treatment, precise imaging of tumor metastasis is required. Here we prepared persistent luminescent nanoparticles (PLNPs) containing a hydrogel (PL-gel) for targeted, sustained, and autofluorescence-free tumor metastasis imaging. PLNPs offered renewable long-lasting near-infrared (NIR) emitting without in situ radiation, favoring deep tissue penetration imaging without background interference. PLNPs were conjugated with 4-carboxyphenyl boronic acid (CPBA) to yield PLNPs-CPBA, which specifically recognized metastatic breast cancer cells (MBA-MD-231 cells) and enabled receptor-mediated endocytosis for specific cancer cell labeling. The PLNPs-CPBA-labeled cancer cells enabled sensitive imaging performance and high viability without influencing the migration and invasiveness of cancer cells for long-term tracking. PLNPs-CPBA were further encapsulated inside alginate to generate PL-gel for sustained PLNPs-CPBA release and tumor cell labeling, and the PL-gel showed enhanced renewable persistent luminescence compared to the PLNPs-CPBA suspension. The metastasis in the mouse breast cancer model was continuously tracked by persistent luminescence imaging, showing that PL-gel achieved noninvasive and highly selective imaging of tumor metastasis without background interference. Our PL-gel could be rationally designed to specifically target other types of cancer cells and thus provide a powerful and generic platform for the study of tumor metastasis.

Background: Zein-based carriers are a promising delivery system for biomedical applications. However, few studies involve systematic investigation on their in vivo biocompatibility and immunogenicity., Purpose: The objective of this study was to identify the immunogenicity, type of immune response, biocompatibility and systemic recall immune response of zein nanoparticles administrated via different routes in mice., Animals and Methods: Female Balb/c mice were selected as the animal model in this paper. The effect of particle size, dose and inoculation routes on immunogenicity were systematically explored. The mice were challenged at week 50 via intramuscular and subcutaneous routes to investigate the systemic recall immune responses of zein nanoparticles. Hematoxylin and eosin staining was performed to investigate the biocompatibility of zein nanoparticles at injection sites., Results: The administration of zein particles by parenteral routes led to a long-term systemic immune response. Particle size did not affect zein-specific IgG antibody titers. IgG antibody titers and inflammatory cell infiltration at the injection sites resulting from intramuscular zein particle injection were significantly higher than those from subcutaneous injection of the same dose. For intramuscular inoculation, dose-dependent IgG antibody titers were observed after the third inoculation, while no significant difference was found via the subcutaneous route. For both routes, IgG titer showed a time-dependent decrease at all dose levels from week 5 onward, and finally plateaued at week 28. The IgG subtype assay showed a predominant Th2-type immune response for both administration routes. Challenge with zein nanoparticles at week 50 led to a significant increase in specific IgG titer at all dose levels, indicating systemic recall immune responses. Interestingly, IgG antibody levels in the subcutaneous groups showed a delayed decrease compared to those of the intramuscular injection groups at all dose levels., Conclusion: This study indicated that immunogenicity may be one of the key challenges of using zein nanoparticles as carriers via parenteral administration. Further investigation is needed to illustrate zein immunogenicity in other forms, and the possible effect of systemic recall immune response on in vivo pharmacokinetic characteristics., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Li et al.)

The effectiveness of active targeting in cancer nanomedicine is becoming increasingly more debatable. Here, the role of the ligand functionalization patterns (number and distribution) on nanoparticle surfaces in tumor targeting is investigated using a 9 nm sized miniferritin protein nanocage, Dps modified with Arg-Gly-Asp (RGD) ligands whose functionalization patterns are precisely controlled. In vitro and in vivo experiments show that RGD modification endows Dps with tumor targeting capacity no matter what the surface pattern is. The tumor targeting of 2-ligand Dps, which is better than that of 1-ligand Dps, rivals or surpasses that of the 12- or 24-ligand Dps. The 12-ligand Dps with clustered RGD distribution shows 2.3 times the in vivo targeting efficiency of that with even distribution. The surface ligand pattern effects are correlated at least to receptor clustering and opsonization. This study provides insights into the understanding of the controversial findings on active tumor targeting in the literature and highlights the necessity of precise functionalization to achieve optimal active targeting in developing cancer nanomedicine., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Lanthanide-doped nanoparticles have long been stereotyped for optical luminescence bioimaging. However, they are known to be unable to produce therapeutic abilities. Here, we describe a lanthanide-based theranostic agent, namely, prussian blue (PB)-coated NaErF4@NaYF4@NaNdF4 core/shell/shell nanocrystals encapsulated in a phospholipid PEG micelle (PEG-CSS@PB), which showed switched imaging and hyperthermia abilities under distinct near infrared (NIR) light activation. The erbium (Er3+)-enriched inner core nanocrystals (NaErF4) enabled the emission of tissue-penetrating luminescence (1525 nm) in the second biological window (NIR-II, 1000-1700 nm), which endowed high-resolution optical imaging of the blood vessels and tumors under ∼980 nm excitation. High neodymium (Nd3+) concentrations in the epitaxial outer NaNdF4 shell introduced maximum cross relaxation processes that converted the absorbed NIR light (∼808 nm) into heat at high efficiencies, thus providing abilities for photothermal therapy (PTT). Importantly, the coated Prussian blue (PB) increased light absorption by about 10-fold compared to the composite free of PB, thus entailing a high light-to-heat conversion efficiency of ∼50.5%. This commensurated with that of well-established gold nanorods. As a result, the PEG-CSS@PB nanoparticles with MTT-determined low toxicities resulted in ∼80% death of HeLa cells at a dose of 600 μg mL-1 under 808 nm laser irradiance (1 W cm-2) for 10 min. Moreover, utilizing the same light dose, a single PTT treatment in tumor-bearing BALB/c mice shrunk the tumor size by ∼12-fold compared to the tumors without treatment. Our results, here, constituted a solid step forward to entitle lanthanide-based nanoparticles as theranostic agents in nanomedicine studies.

With a wide variety of biodistribution measurement techniques reported in the literature, it is important to perform side-by-side comparisons of results obtained with different methods on the same particle platform, to determine differences across methods, highlight advantages and disadvantages, and inform methods selection according to specific applications. Inorganic nanostructured particles (INPs) have gained a central role in the development of injectable delivery vectors thanks to their controllable design, biocompatibility, and favorable degradation kinetic. Thus, accurate determination of in vivo biodistribution of INPs is a key aspect of developing and optimizing this class of delivery vectors. In this study, a systematic comparison of spectroscopy (inductively coupled plasma optical emission spectroscopy), fluorescence (in vivo imaging system, confocal microscopy, and plate reader), and radiolabeling (gamma counter)-based techniques is performed to assess the accuracy and sensitivity of biodistribution measurements in mice. Each method is evaluated on porous silicon particles, an established and versatile injectable delivery platform. Biodistribution is evaluated in all major organs and compared in terms of absolute results (%ID/g and %ID/organ when possible) and sensitivity (σ % ). Finally, we discuss how these results can be extended to inform method selection for other platforms and specific applications, with an outlook to potential benefit for pre-clinical and clinical studies. Overall, this study presents a new practical guide for selection of in vivo biodistribution methods that yield quantitative results. STATEMENT OF SIGNIFICANCE: The significance of this work lies in the use of a single platform to test performances of different biodistribution methods in vivo, with a strict quantitative metric. These results, united with the qualitative comparison of advantages and disadvantages of each technique, are aimed at supporting the rational choice of each different method according to the specific application, to improve the quantitative description of biodistribution results that will be published by others in the future., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Traditional electrochemical hydrogen peroxide (H 2 O 2 ) assays all indispensably require the immobilization of enzyme or nanomaterials on electrode surface. These complex electrode surface modifications are laborious and time-consuming. To overcome such limitations, we developed here a facile homogeneous electrochemical biosensor based on displacement reaction for detection of intracellular and extracellular H 2 O 2 produced by living cells. Methylene blue-labeled short single-stranded DNA strand (DNA-MB) was ingeniously designed as the reporter, which was adsorbed on CeO 2 nanoparticles to result in low electrochemical signal. In the presence of H 2 O 2 , DNA-MB was released from CeO 2 nanoparticles, leading to the significant enhancement of current signal. Therefore, a simple homogeneous electrochemical H 2 O 2 assay is successfully achieved. This strategy also displays excellent anti-interference capability and reproducibility for H 2 O 2 determination. More importantly, this method was capable of conveniently realizing intracellular and extracellular H 2 O 2 assay. Thus, with the excellent merits of simplicity, rapidness, good repeatability, high specific and sensitivity, the proposed strategy has great potential to be applied in exploring the roles of H 2 O 2 in physiological and pathological processes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Expressed in macrophages and endothelial cells, the receptor for angiopoietin, tyrosine kinase with immunoglobulin and epidermal growth factor homology-2 (Tie2), is required for the reconstruction of blood vessels in tumor recurrence after chemotherapy. Thus, small therapeutic peptides that target and block Tie2 activity are promising as a therapeutic for the prevention of tumor relapse after chemotherapy. However, such small peptides often have low bioavailability, undergo rapid enzymatic degradation, and exhibit a short circulation half-life, making them ineffective in cancer therapy. Herein, we designed a dual-responsive amphiphilic peptide (mPEG 1000 -K(DEAP)-AAN-NLLMAAS) to modify the small peptide T4 (NLLMAAS) as a Tie2 inhibitor, endowing it with the ability to endure in circulation and specifically target tumor tissue. The ultimate nanoformulation (P-T4) releases T4 in response to the combination of the acidic tumor microenvironment and the presence of legumain, which is commonly overexpressed in tumor tissue. Compared with free T4, P-T4 decreases vessel density significantly (free T4: 2.44 ± 1.20%, P-T4: 0.90 ± 0.75%), delays tumor regrowth after chemotherapy (free T4: 43.2 ± 11.8%, P-T4: 63.6 ± 13.9%), and reduces distant metastasis formation (free T4: 4.50 ± 2.40%, P-T4: 0.67 ± 0.32%). These effects of P-T4 are produced by the local blockage of Tie2 signals in Tie2-positive macrophages and endothelial cells. In addition to describing a potential strategy to enhance circulation half-life and the accumulation of an active peptide at tumor sites, our approach exemplifies the successful targeting of multiple cell types that overexpress a key molecule in conditions associated with tumors.

Many candidate anticancer drugs have suffered from their intrinsic hydrophobicity, which poses several obstacles for clinical application. To overcome this challenge and further improve the performance, herein a nanocrystal-based biomimetic formulation with a sandwich structure is developed. As the core, flake shaped nanocrystals (NCs) with high loading of the hydrophobic drug hydroxycamptothecin (HCPT) are synthesized via a mild nanoprecipitation process by exploring the template effect of serum albumin. Meanwhile, the camouflaged cancer cell membrane (CM) composed of plentiful membrane proteins endows the NCs with homotypic targeting capacity at tumor sites. In addition, the photosensitizer indocyanine green sandwiched between NCs and CM not only converts near infrared light to heat for photothermal treatment but also improves the dissolution of HCPT NCs for chemotherapy. These features corporately achieve the orchestration of chemo-photothermal combination therapy and completely inhibit tumor growth with few adverse effects, showing promise as a new modality for the utilization of hydrophobic drugs to treat cancer., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Molecule encapsulation in virus-based nanoparticles (VNPs) is an emerging bioinspired way to design novel functional nanostructures and devices. Here, we report a general cargo-compatible approach to encapsulate guest materials based on the apparent critical assembly concentration (CAC app ) of VNPs. Different from the conventional buffer-exchange method, the new method drives the reassembly of VNPs to encapsulate cargoes by simply concentrating an adequately diluted mixture of VNP building blocks and cargoes to a concentration above the CAC app . This method has been proved to work well on different types of cargoes (including inorganic nanoparticles and proteins) and VNPs. The major advantage of this method is that it can maximally preserve cargo stability and activity by providing the freedom to choose cargo-friendly buffer conditions throughout the encapsulation process. This method would benefit the realization of the potentials of VNPs and other protein nanocages as nanomaterials in diverse fields of nanotechnology.

Disulfiram (DSF), an alcohol-aversion drug, has been explored for cancer treatment. Copper diethyldithiocarbamate (Cu(DDC) 2 ) complex formed by DSF and copper ions is a major active ingredient for its anticancer activity. Direct administration of Cu(DDC) 2 is a promising strategy to enhance the anticancer efficacy of DSF. However, efficient drug delivery remains a significant challenge for Cu(DDC) 2 and hinders its clinical use. In this study, we developed a facile stabilized metal ion ligand complex (SMILE) method to prepare Cu(DDC) 2 nanoparticles (NPs). The SMILE method could prepare Cu(DDC) 2 NPs with different types of stabilizers including 1,2-distearoyl- sn-glycerol-3-phosphoethanolamine-poly(ethylene glycol) (PEG) 2000, d-α-tocopherol PEG 1000 succinate, methoxy PEG 5000- b-poly(l-lactide) 5000, and other generally recognized as safe excipients approved by the US Food and Drug Administration. The optimized formulations demonstrated excellent drug-loading efficiency (close to 100%), high drug concentrations (increased drug concentration by over 200-fold compared to the traditional micelle formulation), and an optimal particle size in the sub-100 nm range. Cu(DDC) 2 NPs exhibited outstanding stability in serum for 72 h and can also be stored at room temperature for at least 1 month. The anticancer effects of Cu(DDC) 2 NP formulations were determined by multiple assays including 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, colony-forming assay, calcein-AM/propidium iodide staining, and others. Cu(DDC) 2 NPs showed excellent activity against drug-resistant prostate cancer cells and other cancer cells with a half-maximal inhibitory concentration (IC 50 ) of around 100 nM. Our study also demonstrated that Cu(DDC) 2 NPs induced cell death in drug-resistant prostate cancer cells (DU145-TXR) through paraptosis, which is a nonapoptotic cell death. To our best knowledge, the SMILE method provides, for the first time, a simple yet efficient process for generating Cu(DDC) 2 NPs with high drug concentration, excellent loading efficiency, and desirable physicochemical properties. This method could potentially address drug delivery challenges of DSF/copper-based chemotherapy and facilitate its clinical translation.

Marine microalgae, Platymonas helgolondica var. tsingtaoensis , were used as experimental subjects to study the acute toxic effects of graphene oxide (GO) and dibutyl phthalate (DBP), both individually and together. The growth of algae cells, production of photosynthetic pigments, cell permeability, and oxidative stress were investigated. The effects of GO on the algal toxicity of DBP were evaluated. The results showed that low concentrations of GO (0.1-10 mg·L -1 ) had no significant effect on algae density and chlorophyll production of Platymonas helgolondica var. tsingtaoensis ( P <0.05). However, the algae cell permeability increased significantly with GO concentration ( P <0.05) and reached 2.2 times that of the control group at 10 mg·L -1 . The EC 50, 96 h value of DBP for Platymonas helgolondica var. tsingtaoensis was (11.14±0. 80) mg·L -1 , which, in terms of toxicity, was much higher than that of GO (EC 50, 96 h >100 mg·L -1 ). At a GO concentration of 1 mg·L -1 , the EC 50, 96 h value of DBP decreased to (4.93±2.14) mg·L -1 , showing that low concentrations of GO enhanced the algae toxicity of DBP. When 1 mg·L -1 of GO was added, low concentrations of DBP (0.1-2 mg·L -1 ) did not have any significant effect on algae density, chlorophyll production, cell permeability, ROS, and SOD. However, the inhibitory effects of high concentrations of DPB (4 mg·L -1 ) on algae density and chlorophyll production were enhanced by GO, thereby increasing the average ROS and SOD in algae cells by 21% and 7%, respectively. SEM images showed that GO was the primary factor responsible for increasing the coverage and packing of, and the aggregation effect on, algae cells, which could be the reasons for the increased toxicity of DBP. The results of our study can provide data to reveal the risk of novel carbon nanomaterial pollutants to marine organisms.

Background: MicroRNA-221(miR-221) is frequently dysregulated in cancer. The purpose of this study was to explore whether miR-221 can be used as a potential diagnostic marker or therapeutic target for hepatocellular carcinoma (HCC)., Methods: In this study, we investigated whether miR-221 expression was associated with clini-copathological characteristics and prognosis in HCC patients, and we developed a nanoparticle-based miRNA delivery system and detected its therapeutic efficacy in vitro and in vivo., Results: We found that miR-221 was upregulated in HCC tissues, cell lines and blood of HCC patients. Upregulated miR-221 was associated with clinical TNM stage and tumor capsular infiltration, and showed poor prognosis, suggesting that its suppression could serve as an effective approach for hepatocellular carcinoma therapy. Treatment of HCC cells with nanoparticle/miR-221 inhibitor complexes suppressed their growth, colony formation ability, migration and invasion. In vivo, the growth of the tumors treated by the nanoparticle/miR-221 inhibitor complexes were significantly less than those treated by the nanoparticle/miRNA scramble complexes. In addition, circulating miR-221 may act as a potential tumor biomarker for early diagnosis of HCC, and combined serum miR-221 and AFP detection gave a better performance than individual detection in early diagnosis of HCC., Conclusion: These findings suggest that a nanoparticle-based miRNA delivery system could potentially serve as a safe and effective treatment and miR-221 could also be a potential diagnostic marker for HCC., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The osteogenic differentiation of marrow mesenchymal stem cells (MSCs) is very important for bone tissue regeneration. Nanoscale biomaterials have shown promising effect on the osteogenic differentiation of MSCs. In this study, we investigate the effect of europium doped bioactive glass nanoparticles (BGNEu) on the osteogenic differentiation of human MSCs (hMSCs). The cell attachment and proliferation, alkaline phosphatase activity ( ALP ), collagen I secretion ( COL I ) and osteoblasts-related gene expressions ( Alp , Col I ), Osteopontin ( Opn ), runt-related transcription factor 2 (Runx2) were studied after culture with BGNEu (1%, 3%, 5% in mol%) with and without osteogenic inducing factors. The results showed that BGNEu3 significantly enhanced hMSCs osteogenic differentiation ( ALP activity and COL I secretion) by activating osteogenic genes expressions ( Alp , Col I , Opn , Runx2 ) in absence of osteogenic inducing factor. Enhanced osteogenic genes levels were also found by combining BGNEu3 and osteogenic inducing factors. This study may provide an alternative strategy in designing novel bioactive biomaterials with osteogenic inducing ability for bone tissue regeneration.

Biomimetic fluorescent nanoprobes capable of emitting near-infrared (NIR) fluorescence (λ max ≈ 720 nm) upon excitation of 800 nm light were developed. The key conjugated polymer enabled two-photon absorption and Förster resonance energy transfer (FRET) processes within the nanoprobes, which imparted the nanoprobes with ideal NIR-incoming-NIR-outgoing fluorescence features. The cancer cell membrane (CM) coating endowed these nanoprobes with perfect biocompatibility and highly specific targeting ability to homologous tumors. It was believed that CM encapsulation provided an additional protecting layer for the photoactive components residing in the core of nanoprobes for retaining their intrinsic fluorescing ability in the physiological milieu. The long-term structural integrity, excellent photostability (fluorescence decrease <10% upon 30 min illumination of 800 nm pulse laser), high NIR fluorescence quantum yield (∼20%), and long in vivo circulation time of the target nanoprobes were also confirmed. The ability of these feature-packed nanoprobes for circumventing the challenges of absorption and light scattering caused by cellular structures and tissues was definitely confirmed via in vivo and in vitro experiments. The superior performances of these nanoprobes in terms of fluorescence signaling as well as targeting specificity were verified in intravital fluorescence imaging on tumor-bearing model mice. Specifically, these nanoprobes unequivocally enabled high-resolution visualization of the fine heterogeneous architectures of intravital tumor tissue, which proclaims the great potential of this type of probe for high-contrast fluorescence detection of thick biological samples in practical applications.

A highly efficient and pH-universal hydrogen evolution reaction (HER) electrocatalyst with a sandwich-architecture constructed using zero-dimensional N- and P-dual-doped core-shell Co 2 P@C nanoparticles embedded into a 3 D porous carbon sandwich (Co 2 P@N,P-C/CG) was synthesized through a facile two-step hydrothermal carbonization and pyrolysis method. The interfacial electron transfer rate and the number of active sites increased owing to the synergistic effect between the N,P-dual-doped Co 2 P@C core-shell and sandwich-nanostructured substrates. The presence of a high surface area and large pore sizes improved the mass-transfer dynamics. This nanohybrid showed remarkable electrocatalytic activity toward the HER in a wide pH range with good stability. The computational study and experiments revealed that the carbon atoms close to the N and P dopants on the shell of Co 2 P@N,P-C were effective active sites for HER catalysis and that both Co 2 P and the N,P dopants gave rise to an optimized binding free energy of H on the active sites., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Biodegradable nanoparticles with diameters between 100 nm and 500 nm are of great interest in the contexts of targeted delivery., Objective: The present work provides a review concerning the effect of binary organic solvents together with emulsifier on particle size as well as the influence of particle size on the in vitro drug release and uptake behavior., Methods: The polymeric lipid nanoparticles (PLNs) with different particle sizes were prepared by using binary solvent dispersion method. Various formulation parameters such as binary organic solvent composition and emulsifier types were evaluated on the basis of their effects on particle size and size distribution. PLNs had a strong dependency on the surface tension, intrinsic viscosity and volatilization rate of binary organic solvents and the hydrophilicity/hydrophobicity of emulsifiers. Acetone-methanol system together with pluronic F68 as emulsifier was proved to obtain the smallest particle size. Then the PLNs with different particle sizes were used to investigate how particle size at nanoscale affects interacted with tumor cells., Results: As particle size got smaller, cellular uptake increased in tumor cells and PLNs with particle size of ~120 nm had the highest cellular uptake and fastest release rate. The paclitaxel (PTX)-loaded PLNs showed a size-dependent inhibition of tumor cell growth, which was commonly influenced by cellular uptake and PTX release., Conclusion: The PLNs would provide a useful means to further elucidate roles of particle size on delivery system of hydrophobic drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Zein-based nano/microparticles have been demonstrated to be promising carrier systems for both the food industry and biomedical applications. However, the fabrication of size-controlled zein particles has been a challenging issue. In this study, a modified anti-solvent precipitation method was developed, and the effects of various factors, such as mixing method, solvent/anti-solvent ratio, temperature, zein concentrations and the presence of sodium caseinate (SC) on properties of zein particles were investigated. Evidence is presented that, among the previously mentioned factors, the mixing method, especially mixing rate, could be used as an effective parameter to control the size of zein particles without changing other parameters. Moreover, through fine-tuning the mixing rate together with zein concentration, particles with sizes ranging from nanometers to micrometers and low polydispersity index values could be easily obtained. Based on the size-controlled fabrication method, SC-coated zein nanoparticles could also be obtained in a size-controlled manner by incubation of the coating material with the already-formed zein particles. The resultant nanoparticles showed better performance in both drug loading and controlled release, compared with zein/SC hybrid nanoparticles fabricated by adding aqueous ethanol solution to SC solution. The possible mechanisms of the nanoprecipitation process and self-assembly formation of these nanoparticles are discussed., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Site-specific localization is critical for improving the therapeutic efficacy and safety of drugs. Nanoparticles have emerged as promising tools for localized drug delivery. However, over 90% of systemically injected nanocarriers typically accumulate in the liver and spleen due to resident macrophages that form the mononuclear phagocyte system. In this study, the clinically approved antimalarial agent chloroquine was shown to reduce nanoparticle uptake in macrophages by suppressing endocytosis. Pretreatment of mice with a clinically relevant dose of chloroquine substantially decreased the accumulation of liposomes and silicon particles in the mononuclear phagocyte system and improved tumoritropic and organotropic delivery. The novel use of chloroquine as a macrophage-preconditioning agent presents a straightforward approach for addressing a major barrier in nanomedicine. Moreover, this priming strategy has broad applicability for improving the biodistribution and performance of particulate delivery systems. Ultimately, this study defines a paradigm for the combined use of macrophage-modulating agents with nanotherapeutics for improved site-specific delivery.

A smart targeting drug delivery nanocarrier is successfully constructed based on phototriggered competition of host-guest interaction. The targeting motif, i.e., biotin is first concealed by β-cyclodextrin (β-CD) via host-guest interaction. When the nanoparticles are exposed to UV light, the cleavage of photosensitive groups results in the exposure of adamantane (Ad) groups initially located in the interior of nanoassemblies, and β-CDs capped on biotin ligands can be replaced by Ad because of the higher binding constant between Ad and β-CD than that between biotin and β-CD. The competition of host-guest interaction leads to the recovery of targeting capacity of biotin ligands on the nanocarriers. By virtue of photoregulation, the nanocarriers exhibit controllable ligand-receptor recognition, which is proved by flow cytometry, laser confocal microscopy, and cytotoxicity assay. This strategy has a potential to improve the selectivity and safety of targeting drug delivery systems., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We investigated the efficacy and safety of ultrasound (US)-targeted microbubble (MB) destruction (UTMD)-enhanced delivery of monomethoxypoly(ethylene glycol)-poly(lactic-co-glycolic acid)-poly-L-lysine (mPEG-PLGA-PLL) nanoparticles (NPs) loading Cy3-labelled platelet-derived growth factor BB (PDGF-BB) siRNA to rat retina in vivo. Eighty Wistar rats were divided into five groups (G). The right eyes, respectively, received an intravitreal injection as follows: normal saline (NS) (G1), NPs and NS (G2), NPs and MBs (G3), NPs and NS (G4) and NPs and MBs (G5). In G4 and G5, the eyes were exposed to US for 5 mins. Twenty-four hours after transfection, the uptake and distribution of Cy3-labelled siRNA in rat retina were observed by fluorescent microscope. The percentage of Cy3- labelled siRNA-positive cells was evaluated by flow cytometer. The levels of PDGF-BB mRNA in retinal pigment epithelium (RPE) cells and secreted PDGF-BB proteins were also measured. Hematoxylin and eosin staining and frozen sections were used to observe tissue damage. Our results showed that the number of Cy3-labelled siRNApositive cells in G5 was significantly higher than those of the other groups (P less than 0.05 for all comparisons). The maximum efficiency of siRNA uptake in neural retina was 18.22 +/&#95; 1.67%. In G4 and G5, a small number of Cy3- labelled siRNA-positive cells were also detected in the pigmented cell layer of the retina. NPs loading siRNA delivered with UTMD could more effectively down-regulate the mRNA and protein expression of PDGF-BB than NPs plus US (P=0.014 and P=0.007, respectively). Histology showed no evident tissue damage after UTMDmediated NPs loading siRNA transfection. UTMD could be used safely to enhance the delivery of mPEG-PLGAPLL NPs loading siRNA into rat retina.