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In this study, quercetin (Que) was encapsulated for controlled release during gastrointestinal digestion using zein-soy isolate protein (SPI) composite nanoparticles that were made following an antisolvent precipitation technique. The average particle size of the composite nanoparticles ranged from 182.1 to 230.9 nm, and the polydispersity index (PDI) was small (0.105-0.323). The microstructure revealed that the composite nanoparticles were spherically distributed and that Que. was embedded on the surface of the nanoparticles. Que. has an encapsulation efficiency of up to 93.3 %. Spectrum analysis, molecular docking and zeta potential measurements revealed that the interactions between the composite nanoparticles and Que. occurred mainly through hydrophobic interactions, hydrogen bonding, and electrostatic interactions. Compared with single zein nanoparticles, the composite nanoparticles showed a significant and controlled release of Que. during the whole simulated gastrointestinal digestion process. This study provides a novel method for the development of a controlled-release drug delivery system for controlling the release of Que., 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 © 2024 Elsevier Ltd. All rights reserved.)

The impact of optically active biomaterials on drug delivery remains a vital and hot topic. To reveal special advantages of optically active mesoporous silica nanoparticles in delivering drug in cells, optically active mesoporous silica nanoparticles deliver doxorubicin (DOX) with chiral behavior in cancer cells was studied. The present work focused on two types of optically active mesoporous silica nanoparticles named as levorotatory optically active mesoporous silica nanoparticles (LOA-MSNs) and dextrorotatory optically active mesoporous silica nanoparticles (DOA-MSNs) and examined their effects on cellular DOX delivery in cancer cells. The obtained LOA-MSNs and DOA-MSNs were regular spheres with particle diameters ranging from 200 to 250 nm, and their shell layer was filled with interlaced channels. Our results indicated that LOA-MSNs and DOA-MSNs did not exhibit cytotoxicity towards MCF-7 cells and B16 cells. The cytotoxicity of DOX-loaded LOA-MSNs and DOX-loaded DOA-MSNs were stronger than DOX owing to the synergistic retention and accumulation effect of nanoparticles. More importantly, DOX-loaded DOA-MSNs presented stronger cytotoxicity due to the higher synergistic retention and accumulation effect of DOA-MSNs. These findings suggest that DOA-MSNs with superior cellular delivery of DOX have great potential to advance the development of optical anti-tumor delivery system., (© 2024. Controlled Release Society.)

The limitations associated with conventional cancer treatment modalities, particularly for breast cancer, underscore the imperative for developing safer and more productive drug delivery systems. A promising strategy that has emerged is the combination of chemotherapy with gas therapy. We synthesized curcumin-loaded amorphous calcium carbonate nanoparticles (Cur-CaCO 3 ) via a gas diffusion reaction in the present study. Subsequently, a "one-step" ethanol injection method was employed to fabricate lipid-coated calcium carbonate nanoparticles (Cur-CaCO 3 @LA-Lip) loaded with L-arginine, aimed at harnessing the synergistic effects of chemotherapy and nitric oxide to enhance antitumor efficacy. Transmission electron microscopy analysis revealed that Cur-CaCO 3 @LA-Lip nanoparticles were subspherical with a distinct lipid layer encapsulating the periphery. Fourier transform infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry results confirmed the successful synthesis of Cur-CaCO 3 @LA-Lip. The nanoparticles exhibited significant drug loading capacities of 8.89% for curcumin and 3.1% for L-arginine. In vitro and in vivo assessments demonstrated that Cur-CaCO 3 @LA-Lip nanoparticles facilitated sustained release of curcumin and exhibited high cellular uptake, substantial tumor accumulation, and excellent biocompatibility. Additionally, the nanoparticles showed robust cytotoxicity and potent antitumor efficacy, suggesting their potential as a formidable candidate for breast cancer therapy., (© 2024. The Author(s).)

Vanadium dioxide (VO 2 ) is a class of thermochromic material with potential applications in various fields. Massive production and wide application of VO 2 raise the concern of its potential toxicity to human, which has not been fully understood. Herein, a commercial VO 2 nanomaterial (S-VO 2 ) was studied for its potential toxicity to human embryonic kidney cell line HEK293, and two most common vanadium ions, V(IV) and V(V), were used for comparison to reveal the related mechanism. Our results indicate that S-VO 2 induces dose-dependent cellular viability loss mainly through the dissolved V ions of S-VO 2 outside the cell rather than S-VO 2 particles inside the cell. The dissolved V ions of S-VO 2 overproduce reactive oxygen species to trigger apoptosis and proliferation inhibition via several signaling pathways of cell physiology, such as MAPK and PI3K-Akt, among others. All bioassays indicate that the differences in toxicity between S-VO 2 , V(IV), and V(V) in HEK293 cells are very small, supporting that the toxicity is mainly due to the dissolved V ions, in the form of V(V) and/or V(IV), but the V(V)'s behavior is more similar to S-VO 2 according to the gene expression analysis. This study reveals the toxicity mechanism of nanosized VO 2 at the molecular level and the role of dissolution of VO 2 , providing valuable information for safe applications of vanadium oxides., 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 © 2024 Elsevier B.V. All rights reserved.)

Curcumin (Cur) as a natural pigment and biological component, can be widely used in food and beverages. However, the water insolubility of Cur significantly limits its applications. In this study, we prepared a series of nanocrystals via ultrasound-assisted method to improve the solubility and availability of Cur. The results showed artemisia sphaerocephala krasch polysaccharide (ASKP), gum arabic (GA) and wheat protein (WP) were outstanding stabilizers for nanocryatals except traditional agent, poloxamer 188 (F68). The obtained curcumin nanocrystals (Cur-NC) displayed a rod-shaped, crystal- and nanosized structure, and extremely high loading capacity (more over 80 %, w/w). Compared with raw powder, Cur-NC greatly improved the water solubility and dispersibility, and the slow and complete release of Cur of Cur-NC also endowed them excellent antioxidant capacities even at 10 μg/mL. Importantly, as functional factor additive in beverages (e.g. water and emulsion), Cur-NC could increase the content of Cur to at least 600 μg/mL and retain a good stability. Overall, we provided an effective improvement method for the liposoluble active molecules (e.g. Cur) based on the nanocrystals, which not only tremendously enhanced its water solubility, but also strengthened its bioactivity. Notably, our findings broadened the application of water-insoluble compounds., 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 © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The dense extracellular matrix (ECM) in the pancreatic cancer severely hampers the penetration of nanodrugs, which causes inferior therapeutic efficacy. To address this issue, a multifunctional liposome, namely, Lip-DTI/NO, integrating a type-I photosensitizer DTITBT with glutathione (GSH) or heat-responsive nitric oxide (NO) donor S-nitroso-N-acetyl-D-penicillamine (SNAP) is constructed to deplete the tumor ECM, leading to enhanced drug delivery and consequently improved phototherapy. The loaded DTITBT possesses multiple functions including NIR-II fluorescence imaging, efficient superoxide radical (O 2 •- ) generation and excellent photothermal conversion efficiency, making it feasible for precisely pinpointing the tumor in the phototherapy process. Responding to the intracellular overexpressed glutathione or heat produced by photothermal effect of DTITBT, NO can be released from SNAP. Upon 808 nm laser irradiation, Lip-DTI/NO could selectively induce in situ generation of peroxynitrite anion (ONOO - ) in tumor after cascade processes including O 2 •- production, GSH or heat-triggered NO release, and rapid reaction between O 2 •- and NO. The generated ONOO - could activate the expression of endogenous matrix metalloproteinases which could efficiently digest collagen of tumor ECM, thus facilitating enhanced penetration and accumulation of Lip-DTI/NO in tumor. In vivo evaluation demonstrates the notable therapeutic efficacy via ONOO - -potentiated synergistic photodynamic-photothermal therapies on both subcutaneous and orthotopic pancreatic cancer model., (© 2024 Wiley‐VCH GmbH.)

The development of smart theranostic nanoplatforms has gained great interest in effective cancer treatment against the complex tumor microenvironment (TME), including weak acidity, hypoxia, and glutathione (GSH) overexpression. Herein, a TME-responsive nanoplatform named PMIC Apt /ICG, based on PB:Mn&Ir@CaCO 3 Aptamer /ICG, is designed for the competent synergistic photothermal therapy and photodynamic therapy (PDT) under the guidance of photothermal and magnetic resonance imaging. The nanoplatform's aptamer modification targeting the transferrin receptor and the epithelial cell adhesion molecule on breast cancer cells, and the acid degradable CaCO 3 shell allow for effective tumor accumulation and TME-responsive payload release in situ. The nanoplatform also exhibits excellent PDT properties due to its ability to generate O 2 and consume antioxidant GSH in tumors. Additionally, the synergistic therapy is achieved by a single wavelength of near-infrared laser. RNA sequencing is performed to identify differentially expressed genes, which show that the expressions of proliferation and migration-associated genes are inhibited, while the apoptosis and immune response gene expressions are upregulated after the synergistic treatments. This multifunctional nanoplatform that responds to the TME to realize the on-demand payload release and enhance PDT induced by TME modulation holds great promise for clinical applications in tumor therapy., (© 2023 Wiley-VCH GmbH.)

Lutein is a strong antioxidant with anti-inflammatory, anti-oxidative and cardioprotective effects and could be a promising candidate for the treatment of hypertensive heart disease (HHD), but is not clinically appealing because of its low oral bioavailability and main distribution in the eyes. To address this, a biomimetic drug delivery system-MMLNPs was established by coating macrophage membranes (MMs) onto lutein-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (LNPs). This study characterized the physical properties of biomimetic nanoparticles and examined the targeting capability, therapeutic effects and mechanism, and biosecurity of administering them for cardiac fibrosis therapy in the transverse aortic constriction (TAC) model and in vitro. Transmission electron microscope mapping and dynamic light scattering analysis proved that MMLNPs were spherical nanoparticles camouflaged by a layer of cell membrane and had negative zeta potential. Confocal laser scanning microscopy and flow cytometry analysis showed that MMs on the biomimetic nanoparticles hindered the phagocytosis of macrophages and facilitated the targeting of activated endothelial cells. Ex vivo fluorescence imaging experiments demonstrated the targeting of biomimetic nanoparticles to the injured heart. EdU assay indicated that MMLNPs have the same potential to inhibit angiotensin (Ang) II-induced cardiac fibroblast proliferation as free lutein. Furthermore, echocardiography showed that MMLNPs improved cardiac function and structure, and Masson staining and western blotting showed that MMLNPs ameliorated cardiac fibrosis. We found MMLNPs inhibited the interleukin (IL)-11/ERK signaling pathway which was up-regulated in the TAC model compared to the sham-operated mouse. Biochemical testing and hematoxylin and eosin staining proved that the long-term use of MMLNPs lacked biological toxicity. Collectively, MMLNPs might be a promising nanodrug delivery approach to attenuate pressure overload (PO)-induced cardiac fibrosis., Competing Interests: Declaration of Competing Interest All authors disclosed no relevant relationships., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Lifetime-based NIR luminescent nanothermometry is ideally suited for temperature detection in living cells and in vivo, but the thermal sensitivity ( S r by finely controlling the shell thickness of lanthanide-doped core-shell-shell nanoparticles. Owing to the space-dependent energy transfer and back energy transfer between Nd S r by finely controlling the shell thickness of lanthanide-doped core-shell-shell nanoparticles. Owing to the space-dependent energy transfer and back energy transfer between Nd 3+ and Yb 3+ as well as the energy migration to surface quenchers, both active and inert shells can regulate the thermal-dependent nonradiative decays and NIR luminescence lifetime of Yb 3+ , which in turn modulates the S r from 0.56% to 1.54% °C -1 . After poly(acrylic acid) modification of the optimal architecture, the tiny nanoprobes possess robust stability to fluctuations in the microenvironment, which enables accurate temperature mapping of inflammation in the internal liver organ of living mouse. This work will provide new insights for optimizing S r and guidance for precise temperature measurements in vivo.

Numerous literatures have shown the advantages of Pickering emulsion (PE) for the delivery of bioactive ingredients in the fields of food, medicine, and cosmetics, among others. On this basis, the multi-loading mode of bioactives (internal phase encapsulation and/or loading at the interface) in small molecular bioactives nanocrystal-stabilized PE (BNC-PE) enables them higher loading efficiencies, controlled release, and synergistic or superimposed effects. Therefore, BNC-PE offers an efficacious delivery system. In this review, we briefly summarize BNC-PE fabrication and characterization, with a focus on the processes of possible evolution and absorption of differentially applied BNC-PE when interacting with the body. In addition, methods of monitoring changes and absorption of BNC-PE in vivo, from the nanomaterial perspective, are also introduced. The purpose of this review is to provide an accessible and comprehensive methodology for the characterization and evaluation of BNC-PE after formulation and preparation, especially in relation to biological assessment and detailed mechanisms throughout the absorption process of BNC-PE in vivo., (© 2022 Institute of Food Technologists®.)

In recent years, there have been many exciting developments in the biomedical applications of the macrophage membrane bionic drug delivery system (MM-Bio-DDS). Macrophages, as an important immune cell, are involved in initiating and regulating the specific immune response of the body. Therefore, the inflammatory process related to macrophages is an important goal in the diagnosis and treatment of many diseases. In this review, we first summarise the different methods of preparation, characterisation, release profiles and natural advantages of using macrophages as a drug delivery system (DDS). Second, we introduce the processes of various chronic inflammatory diseases and the role of macrophages in them, specifically clarifying how the MM-Bio-DDS provides a wide and effective treatment for the targeted inflammatory site. Finally, based on the existing research, we propose the application prospect and existing challenges of the MM-Bio-DDS, especially the problems in clinical transformation, to provide new ideas for the development and utilisation of the MM-Bio-DDS in targeted drug delivery for inflammation and the treatment of diseases.

Plasmonic micro/nanobeads exhibit unique physicochemical properties attributed to their localized surface plasmon resonance (LSPR), enabling use in sensitive suspension array assays and matrix-assisted laser deposition/ionization mass spectrometry (MALDI-MS) analysis. Herein, we report a facile method for the preparation of magnetic plasmonic micro/nanobeads by the combination of Shirasu porous glass (SPG) membrane emulsification and polydopamine (PDA)-assisted in-situ reduction. The magnetic responsiveness properties endowed by doped Fe 3 O 4 nanoparticles result in easy and complete separation of unwanted components during the preparation and bio-reaction processes. In addition, the coverage degree of the plasmonic shell can be flexibly controlled. As a result of the significant metal-enhanced fluorescence effect, as-prepared plasmonic microbeads enable the sensitive detection of alpha-fetoprotein (AFP) and deoxyribonucleotide (DNA) in suspension array with detection limits of 0.11 ng mL -1 and 1.65 fmol mL -1 , respectively, 8.6 times and 2 orders of magnitude higher than unmodified microbeads. Furthermore, as-prepared plasmonic nanobeads can be used as a matrix for MALDI-MS to allow the detection of low molecular weight biological molecules. As little as 0.2 pmol of proline and serine can be detected in a sample as small as 0.5 μL. This work provides a general strategy for the design of multifunctional plasmonic micro/nanomaterials that will help promote further advancements in sample analysis., 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.)

Constant oxidative stress and lactate accumulation are two main causes of tumor immunosuppression, their concurrent reduction plays a dominant role in effective antitumor immunity, but remains challenging. Herein, reactive oxygen species (ROS) responsive prodrug nanoparticles (designed as DHCRJ) are constructed for metabolic amplified chemo-immunotherapy against triple-negative breast cancer (TNBC) by modulating oxidative state and hyperglycolysis. Specifically, DHCRJ is prepared by the self-assembly of DOX prodrug-tethered ROS consuming bond-bridged copolymers with the loading of bromodomain-containing protein 4 inhibitor (BRD4i) JQ1. Interestingly, the nanoparticle polymer network could reduce ROS to relieve tumor hypoxia and realize the dense-to-loose structure inversion arising from ROS-triggered network collapse, which favors JQ1 release and hyaluronidase (Hyal)-activatable DOX prodrugs generation. More importantly, disruption of oxidative stress decreases glucose uptake and assists JQ1 to down-regulate oncogene c-Myc driven tumor glycolysis for blocking the source of lactate and reshaping immunosuppressive tumor microenvironment (ITME). Meanwhile, benefiting from the synergistic effect of DOX prodrugs and JQ1, DHCRJ is able to facilitate tumor immunogenicity and potentiate systemic immune responses through antigen processing and presentation pathway. In this manner, DHCRJ significantly suppresses tumor growth and metastasis with prolonged survival. Collectively, this study represents a proof of concept antioxidant-enhanced chemo-immunometabolic therapy strategy using ROS-reducing nanoparticles for efficient synergistic therapeutic modality of TNBC., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Digestive system cancer is the most common cause of cancer death in the world. Although cancer treatment options are increasingly diversified, the mortality rate of malignant cancer of the digestive system remains high. Therefore, it is necessary to explore effective cancer treatment methods. Recently, biomimetic nanoparticle delivery systems based on natural cells that organically integrate the low immunogenicity, high biocompatibility, cancer targeting, and controllable, versatile functionality of smart nanocarrier design with natural cells have been expected to break through the bottleneck of tumor targeted therapy. In this review, we focus on the dynamic changes and complex cellular communications that occur in vivo in natural cells based vehicles. Recent studies on the development of advanced targeted drug delivery systems using the dynamic behaviors such as specific surface protein affinity, morphological changes, and phenotypic polarization of natural cells are summarized. In addition to drug delivery mediated by dynamic behavior, functional "delivery" based on the natural cell themselves is also involved. Aiming to make the best use of the functions of cells, providing clues for the development of advanced drug delivery platforms., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Although synergistic therapy has shown great promise for effective treatment of cancer, the unsatisfactory therapeutic efficacy of photothermal therapy/photodynamic therapy is resulted from the absorption wavelength mismatch, tumor hypoxia, photosensitizer leakage, and inability in intelligent on-demand activation. Herein, based on the characteristics of tumor microenvironment (TME), such as the slight acidity, hypoxia, and overexpression of H 2 O 2 , a TME stimuli-responsive and dual-targeted composite nanoplatform (UCTTD-PC4) is strategically explored by coating a tannic acid (TA)/Fe 3+ nanofilm with good biocompatibility onto the upconversion nanoparticles in an ultrafast, green and simple way. The pH-responsive feature of UCTTD-PC4 remains stable during the blood circulation, while rapidly releases Fe 3+ in the slightly acidic tumor cells, which results in catalyzing H 2 O 2 to produce O 2 and overcoming the tumor hypoxia. Notably, the emission spectrum of the UCTTD perfectly matches the absorption spectrum of the photosensitizer (perylene probe (PC4)) to achieve the enhanced therapeutic effect triggered by a single laser. This study provides a new strategy for the rational design and development of the safe and efficient single near-infrared laser-triggered synergistic treatment platform for hypoxic cancer under the guidance of multimodal imaging., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Nanozymes are promising for precise cancer treatment, but are typically limited in terms of the low catalytic efficiency and the complexity in tumor microenvironment (TME). Herein, we describe a bimodal type of AgPd plasmonic blackbody (AgPd PB) nanozyme of compact sizes (< 30 nm), which presents not only boosted enzyme efficacy but also efficient photothermal therapy (PTT) for synergized therapy through tissue-penetrating light in the second biological window (1000-1700 nm). The synthesized hyperbranched AgPd PB nanozymes possess intense and broadband localized surface plasmonic resonance absorption of 400-1300 nm, entailing prominent photothermal efficiency (η = 45.1% at 1064 nm) for PTT. Importantly, PTT was found to significantly boost the nanozyme efficacy of both catalase (CAT) and peroxidase (POD) processes, which correspondingly decompose H 2 O 2 to into O 2 to relieve tumor hypoxia, and activate H 2 O 2 to generate oxidative •OH radical. While the generated •OH was found to be able to minimize heat shock proteins (HSPs), which plays a vital role to counterbalance PTT effect both in vitro and in vivo. As compared to control ground without treatment, the synergized nanozyme and PTT activities resulted in about 7-fold reduction of tumor volume, thus elevating the survival rate from 0 to 80% at 30 days posttreatment. Besides the synergistic therapy, the AgPd PB nanozyme were shown to own fluorescence, computed tomography (CT), and photoacoustic (PA) imaging abilities, thus having implications for uses in imaging-guided precise cancer therapy. This study provides a paradigm of TME responsive theranostics under NIR-II light irradiation., (© 2022. The Author(s).)

Nanoplastics, as emerging contaminants, may be degraded from microplastics and released into aquatic systems globally, which pose threats to human health via ingestion with food or water. Although plastic fragments have been isolated from placental tissues in pregnant women, little is known about the direct toxicity of nanoplastics on human placental cells that plays a critical role in maintaining healthy growth of fetus. This study explored the mechanistic toxicity of polystyrene nanoplastics (PS-NPs) with different sizes (25, 50, 100 and 500 nm) and surface charges (-NH 2 , -COOH and unlabeled) on human placental cells. Results showed that PS-NPs had size- and surface charge-specific toxicity pattern. The smaller the PS-NP size was, the greater the toxicity induced on human placental cells. In terms of surface charges, NH 2 -labeled PS-NPs caused greater effects on cytotoxicity, inhibition of protein kinase A (PKA) activity, oxidative stress, and cell cycle arrest compared to COOH-labeled and unmodified PS-NPs. PS-NPs also induced size- and surface charge-dependent expression profiles of genes involved in various and interrelated toxicity pathways. In particular, PS-NPs increased intracellular reactive oxygen species in human placental cells, which can induce DNA damage and lead to cell cycle arrest in G1or G2 phase, inflammation and apoptosis. Our findings provide empirical evidences that the negative effects of nanoplastics on human placental cells, and highlight the necessity to conduct risk assessment of nanoplastics on female reproduction and fetal development., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Bacteria-based immunotherapy has become a promising strategy to induce innate and adaptive responses for fighting cancer. The advantages of bacteriolytic tumor therapy mainly lie in stimulation of innate immunity and colonization of some bacteria targeting the tumor microenvironment (TME). These bacteria have cytotoxic proteins and immune modulating factors that can effectively restrain tumor growth. However, cancer is a multifactorial disease and single therapy is typically unable to eradicate tumors. Rapid progress has been made in combining bacteria with nanotechnology. Using the nanomolecular properties of bacterial products for tumor treatment preserves many features from the original bacteria while providing some unique advantages. Nano-bacterial therapy can enhance permeability and retention of drugs, increase the tolerability of the targeted drugs, promote the release of immune cell mediators, and induce immunogenic cell death pathways. In addition, combining nano-bacterial mediated antitumor therapeutic systems with modern therapy is an effective strategy for overcoming existing barriers in antitumor treatment and can achieve satisfactory therapeutic efficacy. Overall, exploring the immune antitumor characteristics of adjuvant clinical treatment with bacteria can provide potential efficacious treatment strategies for combatting cancer., (Copyright © 2022. Published by Elsevier Ltd.)

MicroRNA (miRNA) is a class of small noncoding RNA involved in physiological and pathological processes via the regulation of gene expression. Naked miRNAs are unstable and liable to degradation by RNases. Exosome-like nanoparticles (ELNs) secreted by plants and extracellular vesicles (EVs) found in milk are abundant in miRNAs, which can be carried by ELNs and EVs to target cells to exert their bioactivities. In this review, we describe the current understanding of miRNAs in plant ELNs and milk EVs, summarize their important roles in regulation of inflammation, intestinal barrier, tumors, and infantile immunological functions, and also discuss the adverse effect of EV miRNAs on human health. Additionally, we prospect recent challenges centered around ELN and EV miRNAs for interventional applications and provide insights of grain-derived ELNs and miRNAs interventional use in human health. Overall, plant ELNs and milk EVs can transfer miRNAs to mitigate the pathological status of recipient cells by mediating the expression of target genes but may also exert some side effects. More studies are required to elucidate the in-depth understanding of potential interventional effects of ELN and EV miRNAs on human health.

Accurate and effective tumor diagnosis, detection, and treatment are key for improving the survival rates of patients. Chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable clinical success in eradicating hematologic malignancies. However, the hostile microenvironment in solid tumors severely prevents CAR-T cells from migrating and from infiltrating and killing malignant cells. Tumor microenvironment modulation strategies have attracted much attention in the field of cancer immunotherapy. Multifunctional nanoplatforms that integrate the advantages of different therapeutic techniques can allow for the multimodal synergistic treatment of tumors. In this study, a biocompatible, tumor-targeting, on-demand approach combining CAR-T cell immunotherapy and a chemo-photothermal therapy nanoplatform (FA-Gd-GERTs@Ibrutinib) based on gadolinium-loaded gap-enhanced Raman tags (Gd-GERTs) has been developed for multimodal imaging, and it provides a reliable treatment strategy for solid tumor immunotherapy via microenvironment reconstruction. In our study, folate (FA) receptor targeted molecules are used to improve the accuracy and sensitivity of computed tomography/magnetic resonance/Raman multimodal tumor imaging. The photothermal effect of the nanoprobe can promote the angiogenesis of lymphoma tissue, destroy the extracellular matrix, loosen compact tissue, stimulate chemokine secretion, and effectively enhance the infiltration ability in the case of non-Hodgkin's lymphoma, without dampening the CD19 CAR-T cell activity. The treatment results in tumor-bearing mice proved the existence of excellent synergistic therapy; photothermal therapy improves the accumulation and effector function of CAR-T cells within solid tumors. It is believed that multifunctional nanomaterials with targeted multi-modal imaging capabilities that support combination therapy can provide an efficient route for accurate diagnosis and efficient treatment.

Designing photothermal transducing agents (PTAs) with enhanced photothermal conversion efficiency (PCE) holds essential importance for photothermal tumor eradication applications. Currently, it is an effective way to improve the photothermal efficiency by designing the energy level transition leading to the enhancement of UV absorption. To address the challenge, we develop novel Prussian blue@polyacrylic acid/copper sulfide Janus nanoparticles (PB@PAA/CuS JNPs) via selective coating of PAA nano-hemisphere on one of the surfaces of PB NPs followed by the further formation of CuS on the PAA template. The experiments show that the energy level transition occurs between Janus structure. Besides, it offers enhanced absorption over NIR-I and NIR-II dual windows. The muscle tissue penetration studies suggest that the PB@PAA/CuS JNPs have deeper tissue penetration in the 1064 nm laser irradiation group, indicating their potential for treating deep-tissue-seated tumors. In a word, the unique PB@PAA/CuS JNPs show an enhanced tumor inhibitory effect over the NIR-I and NIR-II dual windows, which will open up new opportunities for improving PTT efficiency by the rational nanostructural design of PTAs., 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 Inc. All rights reserved.)

Signal amplification strategies with spatiotemporally high sensitivity can provide more accurate information and hold great promise for improving the accuracy of disease diagnosis. Herein, a 808 nm near-infrared (NIR) light-activated plasmon enhanced fluorescence-catalytic hairpin assembly (PEF-CHA) signal amplification strategy was proposed for spatiotemporally controllable precise imaging of miRNA in vitro and in vivo with ultrasensitivity. The proposed 808 nm NIR light-activated PEF-CHA signal amplification strategy is constructed through combining up-conversion photocontrol and PEF technologies with CHA. It is worth noting that the laser irradiation-induced overheating effect could be effectively alleviated by using Nd 3+ -sensitized upconversion nanoparticles (UCNPs) to convert 808 nm NIR light to ultraviolet (UV) light, which is almost nondestructive to cells or tissues. In addition, nonspecific activation as well as false positive signals can be effectively avoided. Moreover, the detection limit can be reduced by approximate 38 times thanks to the high sensitivity of the proposed strategy. Furthermore, we demonstrate that the 808 nm NIR light-activated PEF-CHA signal amplification strategy can be expanded to sensitive and activatable imaging of intratumoral miRNAs in living mice, showing feasible prospects for precise biological and medical analysis.

Diagnosis-guided synergistic treatment based on innovative nanomaterials is of great significance for the development of anti-cancer therapies. However, the low delivery efficiency of therapeutic gene and the inability to trigger release on demand are still major obstacles impeding its wide application. Herein, we report an ultra-fast one-step method within 2 min to prepare a smart carrier, liposome-coated Prussian blue @ gold nano-flower, which is named LPAR after linking with tumor-targeting peptide. The versatile LPAR not only can respond to near-infrared (NIR) light, achieve the selective delivery and the controlled release of siRNA targeting the mutant gene of Kras at its codon-12 from Glycine (G) to Aspartic acid (D) (named as G12D mutant gene) in the malignant pancreatic tumors, but also efficiently convert the absorbed NIR light into the heat to realize gene-photothermal synergistic therapy both in vitro and in vivo. Theoretical simulation results reveal that the outstanding photothermal conversion efficiency of LPAR is mainly due to its higher electric field intensity and power density distributions. Furthermore, the LPAR possesses the capabilities for triple-modal imaging. Therefore, the developed NIR light-responsive LPAR has the potential to be served as a tumor-targeted nano-delivery system for imaging-guided synergistic therapy of cancers., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Decarboxylation of low-value fatty acids from biomass is a simple process to produce synthetic fuels suitable to be blended with gasoline or diesel. The present study reports the photocatalytic decarboxylation of octanoic acid in the presence of H 2 by a series of modified TiO 2 to form mixtures of n-heptane and tetradecane as major products in variable proportions, depending on the photocatalyst and the reaction conditions. It was found that the photocatalytic activity increases upon an optimal reductive NaBH 4 treatment, presumably by generation of surface oxygen vacancies and by the deposition of Ni nanoparticles in the appropriate loading. Under the optimized conditions, an almost complete octanoic acid conversion and a combined selectivity to n-heptane and tetradecane over 80 % were reached at 10 h of UV/Vis light irradiation with a 300 W Xe lamp. No changes in the photocatalytic performance were observed for six consecutive runs. The present results illustrate the possibility that photocatalytic decarboxylation offers for the transformation of biomass into synthetic fuels under mild conditions., (© 2021 Wiley-VCH GmbH.)

Background: Insufficient radiofrequency ablation (IRFA) can promote the local recurrence and distal metastasis of residual hepatocellular carcinoma (HCC), which makes clinical treatment extremely challenging. In this study, the malignant transition of residual tumors after IRFA was explored. Then, arsenic-loaded zeolitic imidazolate framework-8 nanoparticles (As@ZIF-8 NPs) were constructed, and their therapeutic effect on residual tumors was studied., Results: Our data showed that IRFA can dramatically promote the proliferation, induce the metastasis, activate the epithelial-mesenchymal transition (EMT) and accelerate the angiogenesis of residual tumors. Interestingly, we found, for the first time, that extensive angiogenesis after IRFA can augment the enhanced permeability and retention (EPR) effect and enhance the enrichment of ZIF-8 nanocarriers in residual tumors. Encouraged by this unique finding, we successfully prepared As@ZIF-8 NPs with good biocompatibility and confirmed that they were more effective than free arsenic trioxide (ATO) in sublethal heat-induced cell proliferation suppression, apoptosis induction, cell migration and invasion inhibition, and EMT reversal in vitro. Furthermore, compared with free ATO, As@ZIF-8 NPs exhibited remarkably increased therapeutic effects by repressing residual tumor growth and metastasis in vivo., Conclusions: This work provides a new paradigm for the treatment of residual HCC after IRFA., (© 2021. The Author(s).)

Arsenic trioxide (ATO, As 2 O 3 ), an active ingredient of traditional Chinese medicine, has been approved by the U.S. Food and Drug Administration as an effective therapeutic agent for acute promyelocytic leukemia (APL). However, the application of ATO in treating advanced solid tumors like hepatocellular carcinoma (HCC) is still restricted by limited therapeutic efficacy and insufferable side effects. To solve this problem, we reported a general and facile strategy using human serum albumin (HSA) as a template for synthesizing a series of ATO-based nanoparticles with uniform single-albumin size. Then, we prepared a multifunctional drug delivery system (MDDS) based on MnAs/HSA termed MnAs/ICG/HSA-RGD, and tested its efficacy both in vitro and in vivo . Our results revealed that the photothermal effect of MnAs/ICG/HSA-RGD can not only cause irreversible damage to the tumor but also accelerate the discharge of As and Mn 2+ ions, enabling responsive chemotherapy and magnetic resonance imaging. Interestingly, the expression of HSP90, vimentin, and MMP-9 in tumor cells was inhibited during the treatment, resulting in less metastasis and recurrence. Moreover, no apparent side effect has been observed during the treatment. Therefore, MnAs/ICG/HSA-RGD can be considered as a promising option for HCC with excellent therapeutic efficacy and minimum side effects.

There has been significant progress with rare-earth coated upconversion nanoparticles (UCNPs) representing a promising new generation of contrast agents for biomedical applications. However, in vivo biological safety remains poorly investigated. This work examined citric acid-UCNP (NaYF4:Yb 3+ /Gd 3+ , ∼ 5 nm, Cit-UCNP) generated as contrast agents for multimodal imaging with concurrent magnetic resonance (MRI) and X-ray computed tomography (CT). We first examined the in vitro cytotoxicity and efficacy of Cit-UCNPs as a contrast agent. We then performed a systematic investigation of their in vivo biodistribution and biocompatibility. Our results noted that Cit-UCNPs have minimal toxicity and demonstrated significant potential as contrast agents for multimodal biomedical imaging. This study indicates Cit-UCNPs could be a valuable addition to enhance long-term targeted diagnostic and prognostic multimodal clinical imaging approaches., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is an inflammation-induced and chemotherapy-resistant common liver cancer, and a major cause of death. Some natural products have been found to be used as photosensitizers in photodynamic therapy of HCC. Due to its specific molecular structure diversities and biological activities, current status of HCC treatment with nature production remains unsatisfactory, owing largely to the toxicity, side effect and inefficiency to drug targeting. Herein, we show a nanoparticle-based broad-spectrum anti-inflammatory strategy that naïve neutrophil membrane-coated PLGA nanoparticles (NM-HB NPs) were constructed for synchronous nearinfrared fluorescence (NIR FL) imaging and photodynamic therapy (PDT) for HCC. Moreover, NM-HB NPs inhibited the expression of JUNB and promoted the ROS production. JUNB depletion enhanced the anti-HCC effect of NM-HB NPs. Importantly, it was shown that NM-HB NPs are well targeted to the tumor site and overcomes the blood circulation and immune elimination in vivo and vitro. In a mouse model of HCC, the neutrophil membrane-coated nanoparticles (NM-HB NPs) show significant therapeutic efficacy by PDT and suppressing tumor tissue increase. All results demonstrated that NM coated HB NPs representing a viable and effective treatment option for HCC., (Copyright © 2021. Published by Elsevier B.V.)

Phototheranostics based on luminogens with aggregation-induced emission (AIE) characteristics is captivating increasing research interest nowadays. However, AIE luminogens are inherently featured by inferior absorption coefficients (ε) resulting from the distorted molecular geometry. Besides, molecular innovation of long-wavelength light-excitable AIE luminogens with highly efficient phototheranostic outputs is an appealing yet significantly challenging task. Herein, on the basis of a fused-ring electron acceptor-donator-acceptor (A-D-A) type molecule (IDT) with aggregation-caused quenching (ACQ) properties, molecular engineering smoothly proceeds and successfully yields a novel AIE luminogen (IDT-TPE) via simply modifying tetraphenylethene (TPE) moieties on the sides of IDT backbone. The AIE tendency endows IDT-TPE nanoparticles with enhanced fluorescence brightness and far superior fluorescence imaging performance to IDT nanoparticles for mice tumors. Moreover, IDT-TPE nanoparticles exhibit near-infrared light-excitable features with a high ε of 8.9 × 10 4 m -1 cm -1 , which is roughly an order of magnitude higher than that of most previously reported AIE luminogens. Combining with their reactive oxygen species generation capability and extremely high photothermal conversion efficiency (59.7%), IDT-TPE nanoparticles actualize unprecedented performance in multimodal phototheranostics. This study thus brings useful insights into the development of versatile phototheranostic materials with great potential for practical cancer theranostics., (© 2021 Wiley-VCH GmbH.)

Doxorubicin is a broad-spectrum antineoplastic drug used in tumor therapy, its clinical application is limited by side effects on normal tissues. In this article, a pH-responsive drug delivery system (NPs(DOX/AFc)) with co-delivers doxorubicin (DOX) and aminoferrocene (AFc) was prepared by a two-step synthesis method including the oxidation of hyaluronic acid and Schiff base reaction. NPs(DOX/AFc) can be used in combination therapy of chemodynamic therapy (CDT) and chemotherapy (CT), thus the dosage of the chemotherapeutic drug DOX was reduced. The drug release behavior of NPs(DOX/AFc) in vitro showed that acid-responsive drug releases under the endosomal/lysosomal environment were 56.5 % of DOX and 61.8 % of AFc. In vitro toxicity experiments showed that DOX and AFc had synergistic effects (CI = 0.878). The results of intracellular ROS measurement and the mitochondrial membrane potential analysis showed that in tumor cells NPs(DOX 4 /AFc) induced more production of reactive oxygen species and more loss of the mitochondrial membrane potential. In short, this co-delivery system based on polymer prodrugs provides a new idea for the combined application of CT and CDT., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Photodynamic therapy (PDT) destroys tumor cells mainly through singlet oxygen ( 1 O 2 ) generated by light-irradiated photosensitizers (PSs). However, the fleeting half-life of 1 O 2 greatly impairs PDT efficacy. Herein, we propose an unreported unsaturated fatty acid (UFA)-assisted PS co-assembly strategy to address this problem. Three UFAs, namely, oleic acid (OA), linoleic acid (LA) and linolenic acid (LNA), are capable of co-assembling with 5,10,15,20-tetrakis(4-aminophenyl)porphyrin (TAPP) into uniform nanoparticles. Under irradiation, TAPP produces 1 O 2 , which directly attacks tumor cells and simultaneously oxidizes UFAs to generate lipid hydroperoxides with sustained damage. Interestingly, the unsaturation degree of UFAs is not only related to their peroxidation rate but also has a remarkable impact on the intracellular TAPP release characteristic of the nanoparticles (NPs). The TAPP-LA NPs could release the cargo rapidly and produce the highest lipid peroxidation and reactive oxygen species levels upon irradiation. Such a unique finding sheds new light on UFA-based combination applications for enhanced photodynamic efficacy by boosting lipid peroxidation., (Copyright © 2021. Published by Elsevier B.V.)

A new type of fluorescent silicon nanoparticles (SiNPs) were prepared via a facile one-pot hydrothermal method by using N-[3-(trimethoxysilyl)propyl]-ethylenediamine (DAMO) and glucose as reagents, and were subsequently applied to construct a ratiometric fluorescence assay for sensitive and rapid determination of xanthine in human serum. Two catalytic oxidation reactions were employed to induce a fluorescence response of the testing system towards xanthine. Under the catalysis of xanthine oxidase (XOD), xanthine in serum samples was oxidized and produced hydrogen peroxide (H 2 O 2 ). By utilizing o-phenylenediamine (OPD) as the substrate for horseradish peroxidase (HRP) in the presence of H 2 O 2 , fluorescent 2,3-diaminophenazine (DAP) was finally generated. A ratiometric fluorescence assay for xanthine was established by determining the ratio of the green-yellow fluorescence emission of DAP and the blue fluorescence emitted from SiNPs under the inner filter effect (IFE) of DAP. Instead of traditional multi-step procedures for adding reacting reagents to the testing solution, all the reaction reagents were mixed with serum samples in a single step for this assay to shorten the total reaction time. This assay demonstrates superiority over a solo DAP fluorescence-based assay as well as other reported methods, with excellent sensitivity and reduced testing time. The strategies proposed in this work for both synthesis and application of fluorescent SiNPs can be used in future fabrication of novel fluorescent probes, especially for sensing biological metabolites involved in H 2 O 2 -generation or consumption reactions.

Rod-shaped nanoparticles have been reported to exhibit improved cellular uptake, intracellular processing and transport through tissues and organs, as compared to spherical nanoparticles. We use C-S-B triblock polypeptides composed of a collagen-like block (C), a silk-like block (S) and an oligolysine domain (B) for one-dimensional co-assembly with siRNA into rod-shaped nanoparticles. Here we investigate these siRNA encapsulating rod-shaped nanoparticles as a gene delivery system. Uptake experiments for C-S-B and C-S-B/siPlk1 particles indicate that these rod-shaped nanoparticles can efficiently deliver siPlk1 into HeLa cells. Moreover, C-S-B/siPlk1 complexes display significant mPlk1 gene knockdown in a dose-dependent manner, causing apoptosis as intended. The lower effectiveness of C-S-B/siPlk1 in inducing cell death as compared to cationic lipid-based formulations is explained by the high lysosome-C-S-B/siPlk1 co-localization ratio, which will need to be addressed in a future redesign of polypeptide sequence. Overall, the non-toxic and unique rod-shaped C-S-B nanoparticles deserve further optimization as a new siRNA delivery system for cancer therapy., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020. Published by Elsevier B.V.)

Nanodiamonds (NDs), which are safe carbon nanomaterials, have been used for the transmission of DNA, proteins and drugs. The feasibility of utilizing NDs to deliver NH 2 -PLGA nanoparticle-encapsulated fig polysaccharides for strongly enhanced immune responses has not been clearly studied. In this study, we aimed to use NDs as carriers to deliver NH 2 -PLGA nanoparticle-encapsulated fig polysaccharides for strongly enhanced immune responses. ND particles with a diameter of 5 nm were functionalized by surface carboxylation and covalently conjugated with NH 2 -PLGA nanoparticle-encapsulated fig polysaccharides. NDs-PLGA-FP/OVA could promote antigen uptake and lymphocyte proliferation, increase the expression levels of MHC II, CD80 and CD86, and upregulate the ratio of Th1/Th2 cells in immunized mice. NDs-PLGA-FP/OVA could also upregulate the IL-17 signalling pathway for further immunological enhancement. NDs-PLGA-FP/OVA induced increased TNF-α, IFN-γ, IL-4, and IL-6 cytokine secretion and the levels of OVA-specific antibodies (IgG). These findings demonstrate that NDs-PLGA-FP/OVA have the potential to serve as an effective vaccine delivery and adjuvant system to induce vigorous and long-term immune responses., (Copyright © 2020. Published by Elsevier B.V.)

Recently, nanoparticles have been widely used in drug and vaccine adjuvant delivery. Dendrobium devonianum Polygonatum (DP), a main biologically active ingredient isolated from Dendrobium devonianum, has been widely used in the clinic as an immunostimulant to stimulate and improve immune responses, contributing to its excellent biological activity. To increase the immune efficacy of DP, macrophage cell membrane-coated drug nanocrystals featuring homologous immune escape, targeting ability and low toxicity are in high demand. In this study, a new drug and vaccine adjuvant delivery system, PEI-MM-PLGA-DP/OVA, was designed and developed. This study aimed to report the macrophage immunomodulatory activity of PEI-modified macrophage cell membrane-coated PLGA nanoparticles encapsulating Dendrobium devonianum polysaccharides. PEI-MM-PLGA-DP/OVA could promote antigen uptake by macrophage and lymphocyte proliferation, increase the expression levels of MHC II, CD80 and CD86, and upregulate the ratio of CD4 + to CD8 + T cells in immunized mice. PEI-MM-PLGA-DP/OVA induced the highest TNF-α, IFN-γ, IL-4, and IL-6 cytokine secretion levels and the levels of OVA-specific antibodies (IgG) compared with the other groups. The above results indicated that PEI-MM-PLGA-DP/OVA had better adjuvant activity than PLGA-DP/OVA and MM-PLGA-DP/OVA., (Copyright © 2020. Published by Elsevier B.V.)

Developing green and sustainable Pickering interfacial catalysts for organic reactions in water is of great importance to both the environment and human health. In this study, Janus-type amphiphilic cellulose nanocrystals (CNCs) were synthesized by the surface modification of hydrophilic CNCs with hydrophobic alkyl chains for efficient Pickering emulsion stabilization. Further deposition of palladium nanoparticles on amphiphilic CNCs provides catalytic activity for organic reactions in water, which occur at the interface of water and the organic reactant phase. Different reactions, hydrogenation and C-C coupling, were performed using the obtained Pickering interfacial catalyst. Excellent results were achieved in both reactions. The catalyst developed in our study is expected to advance the field of environment-friendly catalyst systems for green chemistry.

Reactive oxygen species (ROS)-based photodynamic therapy (PDT) has a widespread application in cancer therapy. Nevertheless, the efficiency of PDT is far from satisfactory. One major impediment is the overexpression of glutathione (GSH) in tumor cells, which could deplete the level of PDT-generated ROS. Herein, we develop a novel type of cytochrome P450 enzyme-mediated auto-enhanced photodynamic co-nanoassembly between clopidogrel (CPG) and photosensitizer pyropheophorbide a (PPa). Methods: In this work, we prepare the co-assembled nanoparticles of CPG and PPa (CPG/PPa NPs) by using one-step precipitation method. The assembly mechanism, drug release behavior, GSH consumption, ROS generation, cellular uptake, cytotoxicity of CPG/PPa NPs are investigated in vitro . The mice bearing 4T1 tumor are employed to evaluate in vivo biodistribution and anti-tumor effect of CPG/PPa NPs. Results: Such CPG/PPa NPs could disrupt the intracellular redox homeostasis, resulting from the elimination of GSH by CPG active metabolite mediated by cytochrome P450 enzyme (CYP2C19). The in vivo assays reveal that CPG/PPa NPs not only increase the drug accumulation in tumor sites but also significantly suppress tumor growth in BALB/c mice bearing 4T1 tumor. With CPG-mediated GSH consumption and PPa-triggered ROS generation, CPG/PPa NPs show the enhanced PDT treatment effect by breaking intracellular redox balance. Conclusion: Our findings provide a valuable knowledge for the rational design of the PDT-based combinational cancer therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Antibodies are the most common affinity reagents for specific target recognition. However, their applications are limited by high cost and low stability. Thus, seeking substitutes for antibodies is of great significance. In this work, we designed a library containing 82 self-assembled nanoparticles (SNPs) based on the self-assembly of β-cyclodextrin polymers and adamantane derivatives, and then screened out eight types of SNPs capable of suppressing the toxicity of melittin using a hemolytic activity neutralization assay. The affinities of the SNPs to melittin were demonstrated using surface plasmon resonance (SPR). As evidenced by cytotoxicity experiments, SNPs could also suppress the toxicity of melittin to other cells. In addition, to verify the universality of our method, 11 types of SNPs capable of neutralizing another toxic peptide, phenolic soluble polypeptide (PSMα3) secreted by Staphylococcus aureus , were selected from the same SNP library. Our self-assembly-based method for the library preparation has the advantages of flexible design, mild experimental condition, and simple operation, which is expected to seek artificial affinity reagents for more species.

Using Caenorhabditis elegans as an animal model, we compared the toxicity between nanopolystyrene and three metal oxide nanoparticles (NPs) (Al 2 O 3 -NPs, TiO 2 -NPs, and SiO 2 -NPs). After exposure from L1-larvae to adult day-1, nanopolystyrene (100 μg/L) reduced brood size and induced severe germline apoptosis, and nanopolystyrene (10-100 μg/L) decreased locomotion behavior, induced obvious reactive oxygen species (ROS) production, and activated noticeable mitochondrial unfolded protein response (mt UPR). Using several endpoints (lethality, development, reproduction, and/or locomotion behavior), we found that nanopolystyrene could induce more severe toxicity than SiO 2 -NPs, although nanopolystyrene did not cause the toxicity comparable to that in Al 2 O 3 -NPs or TiO 2 -NPs exposed nematodes. Our data will be useful for understanding the exposure risk of nanopolystyrene on environmental organisms. Moreover, the detected toxicity difference between nanopolystyrene and three metal oxide NPs were associated with the differences in both induction of oxidative stress and activation of mt UPR in exposed nematodes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Colon carcinomas comprise over two-thirds of all colorectal cancers with an overall 5-year survival rate of 64%, which rapidly decreases to 14% when the cancer becomes metastatic. Depending on the stage of colon carcinoma at diagnosis, patients can undergo surgery to attempt complete tumor resection or move directly to chemotherapy with one or a combination of drugs. As with most cancers, colon carcinomas do not always respond to chemotherapies, so targeted therapies and immunotherapies have been developed to aid chemotherapy. We report the development of a local combination therapy for colon carcinoma whereby chemo- and immunotherapeutic entities are delivered intratumorally to maximize efficacy and minimize off-target side effects. A hydrophobic chemotherapeutic agent, docetaxel (DTX), and cholesterol-modified Toll-like receptor 9 (TLR9) agonist CpG (cho-CpG) oligonucleotide are co-loaded in synthetic HDL (sHDL) nanodiscs. In vivo survival analysis of MC-38 tumor-bearing mice treated intratumorally with DTX-sHDL/CpG (median survival; MS = 43 days) showed significant improvement in overall survival compared to mice treated with single agents, free DTX (MS = 23 days, p < 0.0001) or DTX-sHDL (MS = 28 days, p < 0.0001). Two of seven mice treated with DTX-sHDL/CpG experienced complete tumor regression. None of the mice experienced any systemic toxicity as indicated by body weight maintenance and normal serum enzyme and protein levels. In summary, we have demonstrated that chemo- and immunotherapies can be co-loaded into sHDLs, delivered locally to the tumor, and can be used to improve survival outcomes significantly compared to chemotherapy alone.

Mucus is a viscoelastic biological hydrogel that protects the epithelial surface from penetration by most nanoparticles, which limits the efficiency of oral drug delivery. Pursuing highly efficient, biocompatible, and biodegradable oral drug vehicles is of central importance to the development of promising nanomedicine. Here, we prepared five peptosomes (PSs) with various sizes, shapes, and rigidities based on self-assembly of amphiphilic α-lactalbumin (α-lac) peptides from partial enzymolysis and cross-linking. The mucus permeation of α-lac PSs and release of curcumin (Cur) encapsulated in these PSs were evaluated. Compared with a long nanotube, big nanosphere, small nanosphere, and cross-linked short nanotube, we demonstrated that a short nanotube (SNT) exhibits excellent permeability in mucus, which enables it to arrive at epithelial cells quickly. Besides, SNT exhibits the highest cellular uptake and transmembrane permeability on Caco-2/HT29-MTX (E12) 3D coculture model. In vivo pharmacokinetic evaluation revealed that SNT formulation shows the highest curcumin bioavailability, which is 6.85-folds higher than free Cur. Most importantly, Cur loaded in SNT exhibits the optimum therapeutic efficacy for in vivo treatment of dextran sulfate sodium (DSS)-induced ulcerative colitis. In the end, the mechanism of the high permeability of SNTs through mucus was explained by coarse-grained molecular dynamics simulations, which indicated that short time scale jiggling and flying across pores of mucus network played key roles. These findings revealed the tubular α-lac PSs could be a promising oral drug delivery system targeted to mucosal for improving absorption and bioavailability of hydrophobic bioactive ingredients.

Synthetic high-density lipoprotein (sHDL) nanoparticles composed of apolipoprotein A-I mimetic peptide and phospholipids have been shown to reduce atherosclerosis in animal models. Cholesterol is mobilized from atheroma macrophages by sHDL into the blood compartment and delivered to the liver for elimination. Historically, sHDL drug discovery efforts were focused on optimizing peptide sequences for interaction with cholesterol cellular transporters rather than understanding how both sHDL components, peptide and lipid, influence its pharmacokinetic and pharmacodynamic profiles. We designed two sets of sHDL having either identical phospholipid but variable peptide sequences with different plasma stability or identical peptide and phospholipids with variable fatty acid chain length and saturation. We found that sHDL prepared with proteolytically stable 22A-P peptide had 2-fold longer circulation half-time relative to the less stable 22A peptide. Yet, longer half-life did not translate into any improvement in cholesterol mobilization. In contrast, sHDL with variable phospholipid compositions showed significant differences in phospholipid PK, with distearoyl phosphatidylcholine-based sHDL demonstrating the longest half-life of 6.0 hours relative to 1.0 hour for palmitoyl-oleoyl phosphatidylcholine-based sHDL. This increase in half-life corresponded to an approx. 6.5-fold increase in the area under the curve for the mobilized cholesterol. Therefore, the phospholipid component in sHDL plays a major role in cholesterol mobilization in vivo and should not be overlooked in the design of future sHDL. SIGNIFICANCE STATEMENT: The phospholipid composition in sHDL plays a critical role in determining half-life and cholesterol mobilization in vivo., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

To developing a multiple cancer types targeting drug delivery carrier system, a 28 amino acids from the VAR2CSA was synthesized as the placental CSA-binding peptide (plCSA-BP). Its specific binding ability to cancer cells was tested on cancer tissue array, and the results showed that plCSA-BP could bind to multiple cancer types. Then, the plCSA-BP was used as a guiding peptide to coat nanoparticles synthesized from N-2-HACC (CSA/HACC-NPs) which were loaded with prodigiosin (CSA/HACC-PNPs) or indocyanine green (CSA/HACC-INPs). The cancer cells specific targeting and efficacy of the CSA/HACC-PNPs were tested by different cancer cells in vitro and various cancer xenograft model in vivo. A scramble peptide (SCR) was used as control and synthesized SCR/HACC-PNPs and SCR/HACC-INPs. The results showed that the CSA/HACC-INPs could specifically uptake by JEG-3, PC3 and A594 cells, and the CSA/HACC-PNPs exhibited better anti-cancer activity and lower toxic effect in subcutaneous choriocarcinoma and prostatic tumor models compared with the free prodigiosin, HACC-PNPs and SCR/HACC-PNPs. So, the CSA/HACC-NPs could be used as a specific delivery carrier for multiple cancer types, and provided an alternate treatment option of various cancers with a single recipe., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Developing the natural medicine that allow for the specific targeting cytotoxicity is a very important research area in the development of anti-tumor drugs., Aims and Objectives: This study was conducted to determine the targeted inhibitory effects of luteolin-loaded Her-2-poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) on gastric cancer cells and to delineate the mechanism underlying the inhibition of tumors by luteolin., Materials and Methods: Luteolin-loaded Her-2-PLGA NPs (Her-2-NPs) were prepared, physically and chemically characterized, and their effects on gastric cancer cells were investigated. The rate of NP uptake by cells and the cell morphology were observed using confocal microscopy; the rates of cell proliferation and apoptosis were identified using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay and flow cytometry, respectively; and the mRNA and protein expression levels of forkhead box protein O1 (FOXO1) were determined using quantitative polymerase chain reaction and Western blotting, respectively., Results: Compared with nontargeted microspheres, Her-2-NPs led to significantly enhanced uptake of luteolin by SGC-7901 cells. Luteolin-loaded Her-2-NPs also significantly inhibited the proliferation of gastric cancer cells, weakened their migratory ability, and increased both the mRNA and protein expression levels of FOXO1., Conclusion: Luteolin-loading of Her-2-NPs could potentially be used as a novel anti-cancer drugs for targeted cancer therapy., Competing Interests: None

Dialysis methods are frequently used to determine the in vitro drug release kinetics of nanoparticle drug delivery systems. However, the need for the released drug to diffuse through the dialysis membrane delays its appearance in the sampling compartment. Thus, the apparent drug release data outside the dialysis bag typically does not match the desired release kinetics inside the bag adjacent to the nanocarriers. To address this issue, here we describe a simple approach to determine the actual drug release kinetics from nano drug carriers inside the dialysis bag from the experimental data measured from the sampling compartment. First, a calibration experiment is carried out to determine the diffusion barrier properties of the dialysis membranes. The apparent drug release profile of the nanocarrier is then determined using the dialysis method, and a mathematical model is applied to determine the actual drug release kinetics from the experimental data. The model was tested on DOXIL® (doxorubicin liposomes), and an excellent agreement was found between the predicted and measured drug concentration inside the dialysis membranes. By taking the barrier effects of dialysis membranes into consideration, our model independent of drug carrier not only enables the proper interpretation of the data from dialysis studies but also helps to evaluate the dialysis methodology applied to in vitro drug release assays., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The available and effective therapeutic means to treat choriocarcinoma is seriously lacking, mainly due to the toxic effects caused by chemotherapy and radiotherapy. Accordingly, we developed a method for targeting delivery of chemotherapeutical drugs only to cancer cells, not normal cells, in vivo , by using a synthetic placental chondroitin sulfate (CSA)-binding peptide (plCSA-BP) derived from malarial protein VAR2CSA. A 28 amino acids placental CSA-binding peptide (plCSA-BP) from the VAR2CSA was synthesized as a guiding peptide for tumor-targeting delivery, dendrigraft poly-L-lysines (DGL) was modified with plCSA-BP and served as a novel targeted delivery carrier. Choriocarcinoma was selected to test the effect of targeted delivery carrier, and prodigiosin isolated from Serratia marcescens subsp. lawsoniana was selected as a chemotherapeutical drug and encapsulated in the DGL modified by the plCSA-BP nanoparticles (DGL/CSA-PNPs). DGL/CSA-PNPs had a sustained slow-release feature at pH 7.4, which could specifically bind to the JEG3 cells and exhibited better anticancer activity than that of the controls. The DGL/CSA-PNPs induced the apoptosis of JEG3 cells through caspase-3 and the P53 signaling pathway. DGL/CSA-PNPs can be used as an excellent targeted delivery carrier for anticancer drugs, and the prodigiosin could be an alternative chemotherapeutical drug for choriocarcinoma.

Nonalcoholic fatty liver disease (NAFLD) is the early stage of many metabolic syndromes. The intervention of NAFLD can prevent its further development into severe metabolic syndromes. Given the inefficiency and side effects of chemical drugs for treating NAFLD, the hepatic-targeted nanocarriers loaded with bioactive compounds may offer a more effective and acceptable strategy for eliminating NAFLD. Here we developed hepatic-targeted oxidized starch-lysozyme (OSL) nanocarriers to specifically deliver resveratrol (Res) to liver tissue in order to maximize its therapeutic efficiency. The hepatic targeting was achieved using covalently conjugated galactose (Gal), which is recognized by the asialoglycoprotein receptors specifically expressed in hepatocytes. In steatotic HepG2 cell model, treatment with hepatic-targeted Gal-OSL/Res nanocarriers enhanced the cellular Res uptake and anti-lipogenesis capabilities, and effectively decreased triglyceride accumulation by modulating AMP-activated protein kinase (AMPK)/silent information regulation 2 homolog 1(SIRT1)/fatty acid synthase (FAS)/sterol regulatory element-binding protein-1c (SREBP1c) signaling pathway. In mice, Gal-OSL increased Res delivery into liver tissues and increased their hepatic effective concentration in liver. Most importantly, Gal-OSL/Res nanocarriers effectively reversed NAFLD and recovered hepatic insulin sensitivity of NAFLD mice to the healthy state. Furthermore, Gal-OSL/Res efficiently ameliorated lipid deposition and insulin resistance by modulating AMPK/SIRT1/FAS/SREBP1c signaling pathway and downregulated insulin receptor substrate-1 (IRS-1) phosphorylation at serine 307 in liver. These findings suggested that the hepatic-targeted Gal-OSL nanocarriers delivering Res could potentially serve as a safe and promising platform for NAFLD and other liver related diseases., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Improving the efficacy of nanoparticles (NPs) delivery to tumors is critical for cancer diagnosis and therapy. In our previous work, amphiphilic peptide APPA self-assembled nanocarriers were designed and constructed for cargo delivery to tumors with high efficiency. In this study, we explore the use of APPA self-assembled peptosomes as a nanoparticle adjuvant to enhance the delivery of nanoparticles and antibodies to integrin αvβ3 and neuropilin-1 (NRP1) positive tumors. The enhanced tumor delivery of coadministered NPs was confirmed by better magnetosome (Mag)-based T 2 -weighted magnetic resonance imaging (MRI), liposome-based fluorescence imaging, as well as the improved anti-tumor efficacy of monoclonal antibodies (trastuzumab in this case) and doxorubicin (DOX)-containing liposomes. Interestingly, the improvement is most significant for the delivering of compounds that have active or passive tumor targeting ability, such as antibodies or NPs that have enhanced permeability and retention (EPR) effect. However, for non-targeting small molecules, the effect is not significant. In vitro and in vivo studies suggest that both peptosomes and the coadministered compounds might be internalized into cells through a NRP1 mediated co-endocytosis (CoE) pathway. The improved delivery of coadministered NPs and antibodies to tumors suggests that the coadministration with APPA self-assembled peptosomes could be a valuable approach for advancing αvβ3 and NRP1 positive tumors diagnosis and therapy.

Functional polymeric drug delivery systems have generated enormous interest due to their excellent features. This paper reports the development of a novel pH and redox dual-sensitive polymer for anticancer paclitaxel (PTX) delivery applications. The polymer was prepared by polycondensation of disulfide bond-containing dimethyl l-cystinate (Cys) and polycaprolactone (PCL) oligomer via a pH-responsive imine bond. Using the nanoprecipitation method, the polymer can be formulated as nanoparticles (poly(Cys-PCL)/PTX NPs) with a diameter less than 100 nm, as measured by TEM and DLS. The NPs release PTX significantly faster at mildly acidic pH and high concentrations of GSH, exhibiting almost no burst release under the physiological conditions of plasma. Notably, the NPs efficiently deliver PTX to the tumor cells, which was more cytotoxic to 4T1 cancer cells than the pure PTX alone. In vivo results reveal an excellent tumor inhibiting ability, good drug tolerability and biosafety of poly(Cys-PCL)/PTX NPs. Overall, the poly(Cys-PCL)/PTX NPs platform may have greater potential in enhancing cancer therapy.

In recent years, multimodal imaging nanoprobes with high resolution and high sensitivity capabilities have attracted considerable interest because they could offer complementary diagnostic information that would lead to a more precise diagnosis. Herein, the facile fabrication of Gd-doping magnetic nanoparticles conjugated with the PEGylated fluorescence probe Cy5.5 and the tumor-penetrating peptide RGERPPR (R) has been demonstrated for tri-modality targeted T 1 and T₂-weighted magnetic resonance (MR) and the near-infrared (NIR) fluorescence imaging of hepatocarcinoma-bearing mice. The obtained R-GdMFs nanoparticles with a rational design are water-dispersible, have long-term stability, and have controllable magnetic delivery and excellent biocompatibility with no impact on the cell and major organ functions, as was confirmed by MTT and LDH assay, ROS measurements and H&E staining. Relaxivity measurements show a better T 1 relaxivity ( r 1 ) of 16.49 mM -1 s -1 and a T₂ relaxivity ( r ₂) of 141.98 mM -1 s -1 by mutual enhancement, which realized enhanced T 1 and T₂-weighted in vitro MR imaging, which accumulated in the tumor region due to the mediation of the tumor-penetrating peptide. Meanwhile, the in vivo NIR fluorescence imaging results also revealed that the R-GdMFs could be significantly targeting the tumor tissue with bright NIR fluorescence imaging, which would lead to a more precise diagnosis. These findings indicated that as-synthesized R-GdMFs nanoparticles could be used as a platform for synergistically enhanced T in vivo MR imaging, which accumulated in the tumor region due to the mediation of the tumor-penetrating peptide. Meanwhile, the in vivo NIR fluorescence imaging results also revealed that the R-GdMFs could be significantly targeting the tumor tissue with bright NIR fluorescence imaging, which would lead to a more precise diagnosis. These findings indicated that as-synthesized R-GdMFs nanoparticles could be used as a platform for synergistically enhanced T 1 and T₂-weighted MR/NIR fluorescence multimodality imaging in various biomedical systems.