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Given the inevitable human exposure owing to its increasing production and utilization, the comprehensive safety evaluation of silica nanoparticles (SiNPs) has sparked concerns. Substantial evidence indicated liver damage by inhaled SiNPs. Notwithstanding, few reports focused on the persistence or reversibility of hepatic injuries, and the intricate molecular mechanisms involved remain limited. Here, rats are intratracheally instilled with SiNPs in two regimens (a 3-month exposure and a subsequent 6-week recovery after terminating SiNPs administration) to assess the hepatic effects. Nontargeted lipidomics revealed alterations in lipid metabolites as a contributor to the hepatic response and recovery effects of SiNPs. In line with the functional analysis of differential lipid metabolites, SiNPs activated oxidative stress, and induced lipid peroxidation and lipid deposition in the liver, as evidenced by the elevated hepatic levels of ROS, MDA, TC, and TG. Of note, these indicators showed great improvements after a 6-week recovery, even returning to the control levels. According to the correlation, ROC curve, and SEM analysis, 11 lipids identified as potential regulatory molecules for ameliorating liver injury by SiNPs. Collectively, the work first revealed the reversibility of SiNP-elicited hepatotoxicity from the perspective of lipidomics and offered valuable laboratory evidence and therapeutic strategy to facilitate nanosafety., (© 2024 Wiley‐VCH GmbH.)

Osteoarthritis (OA) is a chronic inflammatory disease characterized by cartilage destruction, synovitis, and osteophyte formation. Disease-modifying treatments for OA are currently lacking. Because inflammation mediated by an imbalance of M1/M2 macrophages in the synovial cavities contributes to OA progression, regulating the M1 to M2 polarization of macrophages can be a potential therapeutic strategy. Basing on the inherent immune mechanism and pathological environment of OA, an immunoglobulin G-conjugated bilirubin/JPH203 self-assembled nanoparticle (IgG/BRJ) is developed, and its therapeutic potential for OA is evaluated. After intra-articular administration, IgG conjugation facilitates the recognition and engulfment of nanoparticles by the M1 macrophages. The internalized nanoparticles disassemble in response to the increased oxidative stress, and the released bilirubin (BR) and JPH203 scavenge reactive oxygen species (ROS), inhibit the nuclear factor kappa-B pathway, and suppress the activated mammalian target of rapamycin pathway, result in the repolarization of macrophages and enhance M2/M1 ratios. Suppression of the inflammatory environment by IgG/BRJ promotes cartilage protection and repair in an OA rat model, thereby improving therapeutic outcomes. This strategy of opsonization involving M1 macrophages to engulf carrier-free BR/JPH203 nanoparticles to suppress inflammation for OA therapy holds great potential for OA intervention and treatment., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Triple negative breast cancer (TNBC) presents a formidable challenge due to its low sensitivity to many chemotherapeutic drugs and a relatively low overall survival rate in clinical practice. Photothermal therapy has recently garnered substantial interest in cancer treatment, owing to its swift therapeutic effectiveness and minimal impact on normal cells. Metal-polyphenol nanostructures have recently garnered significant attention as photothermal transduction agents due to their facile preparation and favorable photothermal properties. In this study, we employed a coordinated approach involving Fe 3+ and apigenin, a polyphenol compound, to construct the nanostructure (nFeAPG), with the assistance of β-CD and DSPE-PEG facilitating the formation of the complex nanostructure. In vitro research demonstrated that the formed nFeAPG could induce cell death by elevating intracellular oxidative stress, inhibiting antioxidative system, and promoting apoptosis and ferroptosis, and near infrared spectrum irradiation further strengthen the therapeutic outcome. In 4T1 tumor bearing mice, nFeAPG could effectively accumulate into tumor site and exhibit commendable control over tumor growth. Futher analysis demonstrated that nFeAPG ameliorated the suppressed immune microenvironment by augmenting the response of DC cells and T cells. This study underscores that nFeAPG encompasses a multifaceted capacity to combat TNBC, holding promise as a compelling therapeutic strategy for TNBC treatment., 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.)

Chronic diabetic wounds pose a serious threat to human health and safety because of their refractory nature and high recurrence rates. The formation of refractory wounds is associated with wound microenvironmental factors such as increased expression of proinflammatory factors and oxidative stress. Bilirubin is a potent endogenous antioxidant, and morin is a naturally active substance that possesses anti-inflammatory and antioxidant effects. Both hold the potential for diabetic wound treatment by intervening in pathological processes. In this study, we developed bilirubin/morin-based carrier-free nanoparticles (BMn) to treat chronic diabetic wounds. In vitro studies showed that BMn could effectively scavenge overproduced reactive oxygen species and suppress elevated inflammation, thereby exerting a protective effect. BMn was then loaded into a collagen/polyvinyl alcohol gel (BMn@G) for an in vivo study to maintain a moist environment for the skin and convenient biomedical applications. BMn@G exhibits excellent mechanical properties, water retention capabilities, and in vivo safety. In type I diabetic mice, BMn@G elevated the expression of the anti-inflammatory factor IL-10 and concurrently diminished the expression of the proinflammatory factor TNF-α in the tissues surrounding the wounds. Furthermore, BMn@G efficiently mediated macrophage polarization from the M1-type to the M2-type, thereby fostering anti-inflammatory effects. Additionally, BMn@G facilitated the conversion of type III collagen fiber bundles to type I collagen fiber bundles, resulting in a more mature collagen fiber structure. This study provides a promising therapeutic alternative for diabetic wound healing., 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.)

Cuproptosis is a novel form of regulated cell death which guarantees to increase the efficacy of existing anticancer treatments that employ traditional apoptotic therapeutics. However, reducing the amount of undesirable Cu ions released in normal tissue and maximizing Cu-induced cuproptosis therapeutic effects at tumor sites are the major challenges. In this study, exploiting the chemical properties of copper ionophores and the tumor microenvironment, a novel method is developed for controlling the valence of copper ions that cause photoinduced cuproptosis in tumor cells. CJS-Cu nanoparticles (NPs) can selectively induce cuproptosis after cascade reactions through H 2 O 2 -triggered Cu 2+ release, photoirradiation-induced superoxide radical (∙O 2 - ) generation, and reduction of Cu 2+ to Cu + by ∙O 2 - . The generated reactive oxygen species can result in glutathione depletion and iron-sulfur cluster protein damage and further augmented cuproptosis. CJS-Cu NPs effectively suppressed tumor growth and downregulated the expression of metastasis-related proteins, contributing to the complete inhibition of lung metastasis. Ultimately, this study suggests novel avenues for the manipulation of cellular cuproptosis through photochemical reactions., (© 2023 Wiley-VCH GmbH.)

Bacterial infection causes lung inflammation and recruitment of several inflammatory factors that may result in acute lung injury (ALI). During bacterial infection, reactive oxygen species (ROS) and other signaling pathways are activated, which intensify inflammation and increase ALI-related mortality and morbidity. To improve the ALI therapy outcome, it is imperative clinically to manage bacterial infection and excessive inflammation simultaneously. Herein, a synergistic nanoplatform (AZI+IBF@NPs) constituted of ROS-responsive polymers (PFTU), and antibiotic (azithromycin, AZI) and anti-inflammatory drug (ibuprofen, IBF) was developed to enable an antioxidative effect, eliminate bacteria, and modulate the inflammatory milieu in ALI. The ROS-responsive NPs (PFTU NPs) loaded with dual-drugs (AZI and IBF) scavenged excessive ROS efficiently both in vitro and in vivo. The AZI+IBF@NPs eradicated Pseudomonas aeruginosa (PA) bacterial strain successfully. To imitate the entry of bacterial-derived compounds in body, a lipopolysaccharide (LPS) model was adopted. The administration of AZI+IBF@NPs via the tail veins dramatically reduced the number of neutrophils, significantly reduced cell apoptosis and total protein concentration in vivo. Furthermore, nucleotide oligomerization domain-like receptor thermal protein domain associated protein 3 (NLRP3) and Interleukin-1 beta (IL-1β) expressions were most effectively inhibited by the AZI+IBF@NPs. These findings present a novel nanoplatform for the effective treatment of ALI., 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.)

Ultrasound, featuring deep tissue penetration and noninvasiveness, offers a new opportunity to activate functional materials in a tumor-selective manner. However, very few direct ultrasound-responsive redox systems are applicable under therapeutic ultrasound (1 MHz). Herein, the investigations on nanoprodrug of DHE@PEG-SS-DSPE are reported, which exhibit glutathione-activated release of dihydroethidium (DHE) in tumor cells. DHE is stable with good biosafety and is transformed into cytotoxic ethidium to induce DNA damage under medical ultrasound irradiation, accompanied by the generation of reactive oxygen species. Further, DHE@PEG-SS-DSPE could effectively induce ferroptosis through glutathione depletion, lipid peroxide accumulation, and downregulation of glutathione peroxidase 4. In vivo studies confirmed that DHE@PEG-SS-DSPE nanoparticles effectively inhibit both the growth of solid tumors and the expression of metastasis-related proteins in mice, thus effectively inhibiting lung metastasis. This DHE-based prodrug nanosystem could lay a foundation for the design of ultrasound-driven therapeutic agents., (© 2023 Wiley-VCH GmbH.)

Photothermal therapy (PTT) is a promising approach to cancer treatment. Heptamethine cyanine (Cy7) is an attractive photothermal reagent because of its large molar absorption coefficient, good biocompatibility, and absorption of near-infrared irradiation. However, the photothermal conversion efficiency (PCE) of Cy7 is limited without ingenious excitation-state regulation. In this study, the photothermal conversion ability of Cy7 is efficiently enhanced based on photo-induced electron transfer (PET)-triggered structural deformation. Three Cy7 derivatives, whose Cl is replaced by carbazole, phenoxazine, and phenothiazine at the meso-position (CZ-Cy7, PXZ-Cy7, and PTZ-Cy7), are presented as examples to demonstrate the regulation of the energy release of the excited states. Because the phenothiazine moiety exhibits an obvious PET-induced structural deformation in the excited state, which quenches the fluorescence and inhibits intersystem crossing of S 1 →T 1 , PTZ-Cy7 exhibits a PCE as high as 77.5%. As a control, only PET occurs in PXZ-Cy7, with a PCE of 43.5%. Furthermore, the PCE of CZ-Cy7 is only 13.0% because there is no PET process. Interestingly, PTZ-Cy7 self-assembles into homogeneous nanoparticles exhibiting passive tumor-targeting properties. This study provides a new strategy for excited-state regulation for photoacoustic imaging-guided PTT with high efficiency., (© 2023 Wiley-VCH GmbH.)

Immunotherapy is an advanced therapeutic strategy of cancer treatment but suffers from the issues of off-target adverse effects, lack of real-time monitoring techniques, and unsustainable response. Herein, an ultrasmall Au nanocluster (NC)-based theranostic probe is designed for second near-infrared window (NIR-II) photoluminescence (PL) imaging-guided phototherapies and photoactivatable cancer immunotherapy. The probe (Au 44 MBA 26 -NLG for short) is composed of atomically precise and NIR-II emitting Au 44 MBA 26 NCs (here MBA denotes water-soluble 4-mercaptobenzoic acid) conjugated with immune checkpoint inhibitor 1-cyclohexyl-2-(5H-imidazo[5,1- a ]isoindol-5-yl)ethanol (NLG919) via a singlet oxygen ( 1 O 2 )-cleavable linker. Upon NIR photoirradiation, the Au 44 MBA 26 -NLG not only enables NIR-II PL imaging of tumors in deep tissues for guiding tumor therapy but also allows the leverage of photothermal property for cancer photothermal therapy (PTT) and the photogenerated 1 O 2 for photodynamic therapy (PDT) and releasing NLG919 for cancer immunotherapy. Such a multiple effect modulated by Au 44 MBA 26 -NLG prompts the proliferation and activation of effector T cells, upshifts systemic antitumor T-lymphocyte (T cell) immunity, and finally suppresses the growth of both primary and distant tumors in living mice. Overall, this study may provide a promising theranostic nanoplatform toward NIR-II PL imaging-guided phototherapies and photoactivatable cancer immunotherapy.

Cancer, a disease notorious for its difficult therapy regimen, has long puzzled researchers. Despite attempts to cure cancer using surgery, chemotherapy, radiotherapy, and immunotherapy, their effectiveness is limited. Recently, photothermal therapy (PTT), a rising strategy, has gained attention. PTT can increase the surrounding temperature of cancer tissues and cause damage to them. Fe is widely used in PTT nanostructures due to its strong chelating ability, good biocompatibility, and the potential to induce ferroptosis. In recent years, many nanostructures incorporating Fe 3+ have been developed. In this article, we summarize PTT nanostructures containing Fe and introduce their synthesis and therapy strategy. However, PTT nanostructures containing Fe are still in their infancy, and more effort must be devoted to improving their effectiveness so that they can eventually be used in clinics., 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.)

Oxaliplatin (OXA) resistance remains the major obstacle to the successful chemotherapy of colorectal cancer (CRC). As a self-protection mechanism, autophagy may contribute to tumor drug resistance, therefore autophagy suppression could be regarded as a possible treatment option in chemotherapy. Cancer cells, especially drug-resistant tumor cells, increase their demand for specific amino acids by expanding exogenous supply and up-regulating de novo synthesis, to meet the needs for excessive proliferation. Therefore, it is possible to inhibit cancer cell proliferation through pharmacologically blocking the entry of amino acid into cancer cells. SLC6A14 (ATB 0,+ ) is an essential amino acid transporter, that is often abnormally up-regulated in most cancer cells. Herein, in this study, we designed oxaliplatin/berbamine-coloaded, ATB 0,+ -targeted nanoparticles ((O + B)@Trp-NPs) to therapeutically target SLC6A14 (ATB 0,+ ) and inhibit cancer proliferation. The (O + B)@Trp-NPs utilize the surface-modified tryptophan to achieve SLC6A14-targeted delivery of Berbamine (BBM), a compound that is found in a number of plants used in traditional Chinese medicine, which could suppress autolysosome formation though impairing autophagosome-lysosome fusion. We verified the feasibility of this strategy to overcome the OXA resistance during colorectal cancer treatment. The (O + B)@Trp-NPs significantly inhibited the proliferation and decreased the drug resistance of resistant colorectal cancer cells. In vivo, (O + B)@Trp-NPs greatly suppressed the tumor growth in tumor-bearing mice, which is consistent with the in vitro data. This research offers a unique and promising chemotherapeutic treatment for colorectal cancer., 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.)

In this study, CNFs were provided by an efficient, unmodified, and clean biological method with enzymes and a small amount of alkali, compared to the CNCs with the chemical method involving a strong acid. To provide an accurate targeted selection for future applications, we made the following comparison by analyzing the differences in the preparation method, performance, and application performance of the two nanocelluloses. The result of this study indicated that CNFs and CNCs exhibited a crystallinity index of 58.2 and 83.5%, respectively. CNFs had a mean length ( L ) of 192.3 nm and a diameter (D) of 1.9 nm, and the average L and D of CNCs reached 123.6 nm and 3.7 nm, respectively. The solution viscosity of CNFs and CNCs reached 7.46 Pa s and 1.91 Pa s, respectively. CNFs and CNCs exhibited zeta potential values of -88.26 mV and -26.40 mV, respectively. The electrospun composite film of PLA-CNFs and PLA-CNCs achieved water contact angles of 138.7 and 34.5°, and the water-oil contact angle reached 24.7 and 30.5°, respectively. The breaking strength of PLA-CNFs and PLA-CNCs reached 96.07 cN and 163.23 cN, and the break elongation followed an order of PLA-CNCs (32.16%) < PLA-CNFs (34.70%). In brief, CNFs can make the composite membrane hydrophobic and with superior extension, and CNCs can make the composite membrane hydrophilic and enhance its strength. Both the composite films conformed to the non-toxic standard, and the PLA-CNFs film more significantly contributed to the cell growth, which is expected to serve as a medical material.

Psoriasis is an immune-mediated chronic inflammatory skin disorder characterized by epidermal hyperplasia and infiltration of inflammatory cells. Even though the pathogenesis remains unclear, T helper 17 (Th17) cells-mediated inflammation and keratinocyte-involved proliferation are considered to play key roles during the occurrence and the development of psoriasis. Therefore, suppressing the infiltration/function of Th17 and the abnormal hyperplasia of keratinocytes can be a rational strategy for ameliorating and treating psoriasis. In this study, a self-assembly nanoparticle (BVn) is developed with bilirubin (an endogenous antioxidant) and V9302 (a blocker of ASCT2, an amino acid transporter mediating glutamine influx for providing energy and activating mammalian target of rapamycin [mTOR] pathway) to intervene the local metabolism and alleviate oxidative stress for psoriasis treatment. BVn effectively suppresses inflammatory keratinocyte proliferation and scavenges excess reactive oxygen species (ROS). In the in vivo psoriasis mouse model, BVn shows increased permeation and delayed retention in the psoriatic lesion and reverses the psoriasis-related symptoms, evidenced by the normalized keratinocyte condition and decreased Th17 infiltration/activation. Mechanism study indicates that BVn not only cut off the energy supply but also suppressed cell proliferation or lymph cell expansion by deactivating mTOR pathway, besides alleviated oxidative stress. BVn-based glutamine metabolism modulation strategy offers a promising strategy for psoriasis therapy., (© 2023 Wiley-VCH GmbH.)

Ovarian cancer is one of the most common malignant tumors in gynecology with a high incidence. Combination therapy, eg, administration of paclitaxel followed by a platinum anticancer drug is recommended to treat ovarian cancer due to its advantages in, eg, reducing side effects and reversing (multi)drug-resistance compared to single treatment. However, the benefits of combination therapy are often compromised. In chemo and chemo/gene combinations, co-deposition of the combined therapeutics in the tumor cells is required, which is difficult to achieve due to dramatic pharmacokinetic differences between combinational agents in free forms. Moreover, some undesired properties such as the low-water solubility of chemodrugs and the difficulty of cellular internalization of gene therapeutics also hinder the therapeutic potential. Delivery of dual or multiple agents by nanoparticles provides opportunities to tackle these limits. Nanoparticles encapsulate hydrophobic drug(s) to yield aqueous dispersions facilitating its administration and/or to accommodate hydrophilic genes facilitating its access to cells. Moreover, nanoparticle-based therapeutics can not only improve drug properties (eg, in vivo stability) and ensure the same drug disposition behavior with controlled drug ratios but also can minimize drug exposure of the normal tissues and increase drug co-accumulation at targeted tissues via passive and/or active targeting strategies. Herein, this work summarizes nanoparticle-based combination therapies, mainly including anticancer drug-based combinations and chemo/gene combinations, and emphasizes the advantageous outcomes of nanocarriers in the combination treatment of ovarian cancer. In addition, we also review mechanisms of synergetic effects resulting from different combinations., Competing Interests: The authors declare no conflict of interest., (© 2023 Wu et al.)

To address consumer-level food waste, and pollution from commercial plastics, we developed intelligent films using sodium alginate (SA), pectin (PC), cellulose nanocrystals (CNCs), and anthocyanins extracted from red cabbage (RCA). We also investigated two methods of reinforcing these films - cross-linking (CL), and the addition of CNCs. Both together and separately, these methods improved SA/PC films' mechanical properties and thermal stability. The optimal SA/PC/CNCs/RCA/CL films exhibited pH-dependent color-response properties and high water resistance. These were then tested as colorimetric freshness indicators for shrimp samples, both through seepage and the monitoring of volatile compounds. The colors of the indicators changed from lilac to dark green to greenish-yellow after storage at 25 °C for 72 h, whereas at 4 °C, they changed much more slowly over the same time period. This demonstrated the excellent potential of such films to reduce food waste by providing real-time warnings of pH variation resulting from spoilage., 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.)

Photoluminescence (PL) imaging has become a fundamental tool in disease diagnosis, therapeutic evaluation, and surgical navigation applications. However, it remains a big challenge to engineer nanoprobes for high-efficiency in vivo imaging and clinical translation. Recent years have witnessed increasing research efforts devoted into engineering sub-10 nm ultrasmall nanoprobes for in vivo PL imaging, which offer the advantages of efficient body clearance, desired clinical translation potential, and high imaging signal-to-noise ratio. In this review, we present a comprehensive summary and contrastive discussion of emerging ultrasmall luminescent nanoprobes towards in vivo PL bioimaging of diseases. We first summarize size-dependent nano-bio interactions and imaging features, illustrating the unique attributes and advantages/disadvantages of ultrasmall nanoprobes differentiating them from molecular and large-sized probes. We also discuss general design methodologies and PL properties of emerging ultrasmall luminescent nanoprobes, which are established based on quantum dots, metal nanoclusters, lanthanide-doped nanoparticles, and silicon nanoparticles. Then, recent advances of ultrasmall luminescent nanoprobes are highlighted by surveying their latest in vivo PL imaging applications. Finally, we discuss existing challenges in this exciting field and propose some strategies to improve in vivo PL bioimaging and further propel their clinical applications.

The metabolic associated fatty liver disease (MAFLD) is a public health challenge, leading to a global increase in chronic liver disease. The respiratory exposure of silica nanoparticles (SiNPs) has revealed to induce hepatotoxicity. However, its role in the pathogenesis and progression of MAFLD was severely under-studied. In this context, the hepatic impacts of SiNPs were investigated in vivo and in vitro through using ApoE -/- mice and free fatty acid (FFA)-treated L02 hepatocytes. Histopathological examinations and biochemical analysis showed SiNPs exposure via intratracheal instillation aggravated hepatic steatosis, lipid vacuolation, inflammatory infiltration and even collagen deposition in ApoE -/- mice, companied with increased hepatic ALT, AST and LDH levels. The enhanced fatty acid synthesis and inhibited fatty acid β-oxidation and lipid efflux may account for the increased hepatic TC/TG by SiNPs. Consistently, SiNPs induced lipid deposition and elevated TC in FFA-treated L02 cells. Further, the activation of hepatic oxidative stress was detected in vivo and in vitro, as evidenced by ROS accumulation, elevated MDA, declined GSH/GSSG and down-regulated Nrf2 signaling. Endoplasmic reticulum (ER) stress was also triggered in response to SiNPs-induced lipid accumulation, as reflecting by the remarkable ER expansion and increased BIP expression. More importantly, an UPLC-MS-based metabolomics analysis revealed that SiNPs disturbed the hepatic metabolic profile in ApoE -/- mice, prominently on amino acids and lipid metabolisms. In particular, the identified differential metabolites were strongly correlated to the activation of oxidative stress and ensuing hepatic TC/TG accumulation and liver injuries, contributing to the progression of liver diseases. Taken together, our study showed SiNPs promoted hepatic steatosis and liver damage, resulting in the aggravation of MAFLD progression. More importantly, the disturbed amino acids and lipid metabolisms-mediated oxidative stress was a key contributor to this phenomenon from a metabolic perspective., Competing Interests: Declaration of competing interest All the authors have no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Acute liver injury is a common clinical disease, which easily leads to liver failure and endangers life, seriously threatening human health. Naringenin is a natural flavonoid that holds therapeutic potential against various liver injuries; however it has poor water solubility and bioavailability. In this study, we aimed to develop naringenin-loaded bovine serum albumin nanoparticles (NGNPs) and to evaluate their hepatoprotective effect and underlying mechanisms against acetaminophen overdose toxicity. In vitro data indicated that NGNPs significantly increased the drug solubility and also more effectively protected the hepatocyte cells from oxidative damage during hydrogen peroxide exposure or lipopolysaccharide (LPS) stimulation. In vivo results confirmed that NGNPs showed an enhanced accumulation in the liver tissue. In the murine model of acetaminophen-induced hepatotoxicity, NGNPs could effectively alleviate the progression of acute liver injury by reducing drug overdose-induced levels of oxidative stress, inflammation and apoptosis in hepatocytes. In conclusion, NGNPs has strong hepatoprotective effects against acetaminophen induced acute liver injury.

Chronic lead poisoning has become a major factor in global public health. Chelation therapy is usually used to manage lead poisoning. Dimercaptosuccinic acid (DMSA) is a widely used heavy metal chelation agent. However, DMSA has the characteristics of poor water solubility, low oral bioavailability, and short half-life, which limit its clinical application. Herein, a long-cycle slow-release nanodrug delivery system was constructed. We successfully coated the red blood cell membrane (RBCM) onto the surface of dimercaptosuccinic acid polylactic acid glycolic acid copolymer (PLGA) nanoparticles (RBCM-DMSA-NPs), which have a long cycle and detoxification capabilities. The NPs were characterized and observed by particle size meters and transmission electron microscopy. The results showed that the particle size of RBCM-DMSA-NPs was approximately 146.66 ± 2.41 nm, and the zeta potential was - 15.34 ± 1.60 mV. The homogeneous spherical shape and clear core-shell structure of the bionic nanoparticles were observed by transmission electron microscopy. In the animal tests, the area under the administration time curve of RBCM-DMSA-NPs was 156.52 ± 2.63 (mg/L·h), which was 5.21-fold and 2.36-fold that of free DMSA and DMSA-NPs, respectively. Furthermore, the median survival of the RBCM-DMSA-NP treatment group (47 days) was 3.61-fold, 1.32-fold, and 1.16-fold for the lead poisoning group, free DMSA, and DMSA-NP groups, respectively. The RBCM-DMSA-NP treatment significantly extended the cycle time of the drug in the body and improved the survival rate of mice with chronic lead poisoning. Histological analyses showed that RBCM-DMSA-NPs did not cause significant systemic toxicity. These results indicated that RBCM-DMSA-NPs could be a potential candidate for long-term chronic lead exposure treatment., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The adverse effects of amorphous silica nanoparticles (SiNPs) exposure on the respiratory system were increasingly recognized, however, its potential pathogenesis still remains not fully elucidated. So, this study aimed to explore its effects on pulmonary injury, and to investigate related mechanisms. Histological investigations illustrated SiNPs triggered the lung injury, mainly manifested as alveolar structure destruction, collagen deposition, and mitochondrial ultrastructural injury. In particular, SiNPs greatly enhanced pulmonary ROS and TUNEL positive rate in lungs, both of which were positively correlated with lung impairments. Further, the underlying mechanisms were investigated in cultured human bronchial epithelial cells (16HBE). Consistent with the in vivo findings, SiNPs caused the impairments on mitochondrial structure, as well as the activation of ROS generation and oxidative injury. Upon SiNPs stimuli, mitochondrial respiration was greatly inhibited, while Ca 2+ overload in cytosol and mitochondria owing to ER calcium release was noticed, resulting in mitochondrial-dependent epithelial apoptosis. More importantly, mitochondrial dynamics was imbalanced toward a fission type, as evidenced by upregulated DRP1 and its phosphorylation at Ser616 (DRP1 s616 ), while downregulated DRP1 s637 , and also MFN1, MFN2. Mechanistic investigations revealed that the activation of ROS/Ca 2+ signaling promoted DRP1-mediated mitochondrial fission by SiNPs, forming a vicious cycle, and ultimately contributing to apoptosis in 16HBE. In summary, our results disclosed SiNPs caused pulmonary injury through the induction of epithelial apoptosis via a ROS/Ca 2+ /DRP1-mediated mitochondrial fission axis.

Osteoarthritis (OA) is a chronic disease caused by joint inflammation. Its occurrence and development depend on a continuous inflammation environment. The activated M1 macrophages play a critical role in the inflammatory response of OA. Regulating the pro-inflammatory M1 to anti-inflammatory M2 macrophages in the OA articular cavity could be a rational strategy for OA treatment. It has been acknowledged that activated macrophages could proactively capture opsonized nanoparticles in the bloodstream and then accumulate into the reticuloendothelial system (RES) organs. Based on this fact, a trapping strategy is proposed, which transforms a normal nanoparticle into an opsonized attractant to target and regulate macrophage polarization. In this study, the opsonized nanoparticle (IgG/Bb@BRPL) had several key features, including an immunoglobulin IgG (the opsonized layer), an anti-inflammatory agent berberine (Bb), and an oxidative stress-responsive bilirubin grafted polylysine biomaterial (BR-PLL) for drug loading (the inner nanocore). In vitro studies confirmed that IgG/Bb@BRPL prefer to be phagocytosed by M1 macrophage, not M0. And the internalized IgG/Bb@BRPL effectively promoted macrophage polarization toward the M2 phenotype and protected nearby chondrocytes. In vivo studies suggested that IgG/Bb@BRPL significantly enhanced therapeutic outcomes by suppressing inflammation and promoting cartilage repair while not prolonging the retention period compared to non-opsonized counterparts. This proof-of-concept study provided a novel opsonization trapping strategy for OA drug delivery and treatment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Biology exploits a transcription-translation approach to deliver structural information from DNA to the protein-building machines with high precision. Here, we show how the structural information of small synthetic molecules could be used to guide the assembly of inorganic nanoparticles into diversified yet long-range ordered superstructures, enabling the information transfer across four or five orders of magnitude in length scale. We designed three perylene diimide (PDI) based isomers differing by their site-specific substitutions of the methyl group, which were able to supramolecularly polymerize into diverse structures. Importantly, coassembly of these PDI isomers with nanoparticles (NPs) could produce diverse long-range ordered nanoparticle superstructures, including one-dimensional NPs chains, double helical NPs assemblies and two-dimensional NPs superlattices. Equally important, we demonstrate that the information originated from small molecules could diversify the functions of the self-assembled nanocomposites., (© 2022 Wiley-VCH GmbH.)

Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effects in malignant tumors, the light-controlled drug release, synergism and biocompatibility of current nanocarriers are limited. Herein, we report a red light-responsive, self-destructive carrier constructed using polyethylene glycol-modified, diselenide-bridged mesoporous silica nanoparticles. The carrier is co-encapsulated with the chemo-drug doxorubicin and the photosensitizer methylene blue for chemo-photodynamic therapy. Upon low-dose red light irradiation during photodynamic therapy (PDT), the reactive oxygen species (ROS) mediates a diselenide bond cleavage resulting in the degradation of the organosilica matrix and a dual drug release. This, in turn, results in a synergistic chemo-photodynamic performance in vitro and in vivo. More importantly, such cascade chemo-PDT boosts immunogenic cell death and robust anti-tumor immunity responses. Combination with a PD-1 checkpoint blockade further evokes a series of systemic immunity responses that suppress distant tumor growth and the pulmonary metastasis of breast cancer, as well as offer long-term protection against recurrent tumors. The presented work offers a controllable self-destruction nanoplatform for cascade-amplifying chemo-photodynamic therapy in response to external red light radiation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Due to the low bioavailability and severe toxic side effects caused by the lack of selectivity of traditional chemotherapy drugs, the targeted delivery of chemotherapy drugs has become the key to tumor treatment. The activity and transmembrane potential of mitochondria in cancer cells were significantly higher than that of normal cells, making them a potential target for chemotherapeutic drug delivery. In this study, triphenylphosphine (TPP) based mitochondria targeting polylactic acid (PLLA) nanoparticles (TPP-PLLA NPs) were synthesized to improve the delivery efficiency of anticancer drugs. The carrier material was characterized by 1 H NMR and FT-IR and 7-hydroxyl coumarin (7-HC) was successfully loaded into TPP-PLLA to form 7-HC/TPP-PLLA NPs. Further studies showed that TPP-PLLA NPs were primarily accumulated in the mitochondrial and 7-HC/TPP-PLLA NPs had higher antitumor activity. Taken together, our results indicated that TPP-PLLA NPs could be a promising mitochondria-targeted drug delivery system for cancer therapy.

Chromium poisoning has become one of the most common heavy metal poisoning occupational diseases with high morbidity and mortality. However, most antidotes detoxify the whole body and are highly toxic. To achieve hepato-targeted chromium poisoning detoxification, a novel hepato-targeted strategy was developed using aging erythrocyte membranes (AEMs) as biomimetic material coated with a dimercaptosuccinic acid (DMSA) nanostructured lipid carrier to construct a biomimetic nano-drug delivery system. The particle size, potential, drug loading, encapsulation rate, in vitro release, and stability of the nanoparticles (NPs) were characterized. Confocal microscopy and flow cytometry showed that the prepared NPs could be phagocytized by RAW264.7 macrophage cells. The efficacy of AEM-DMSA-NPs for targeted liver detoxification was evaluated by in vitro MTT analysis and an in vivo model of chromium poisoning. The results showed that the NPs could safely and efficiently achieve targeted liver chromium poisoning detoxification. All the results indicated that the biomimetic nano-drug delivery system mediated by aging erythrocyte membranes and containing DMSA nanoparticles could be used as a novel therapeutic drug delivery system potentially targeting liver detoxification.

With the development of nanomedicine, studies focus on self-assembled nanoplatforms to reduce the toxicity of paclitaxel (PTX), promote the immune function at low-toxicity PTX, and achieve tumor synergistic therapy. Herein, a new nanoplatform was prepared with self-assembled 5-hydroxydopamine (DA)-PTX@tannic acid (TA)-Fe 3+ nanoparticles (TDPP NPs) by consolidation of targeted DA-PTX and TA with the assistance of coordination between polyphenols and Fe 3+ . The polyphenol-based TDPP NPs can reduce the toxicity of PTX and thereby realize the in vitro and in vivo synergistic effect against tumors. The low-toxicity TDPP NPs can enhance the expression of CD40 immune protein. Moreover, the TDPP NPs possessed a small size (52.2±4 nm), high drug loading efficiency (95%), and stable pharmacokinetics, ensuring high tumor accumulation of TDPP NPs by enhanced permeability and retention effect. Our work sheds new light on the nanoformulation of PTX with low toxicity and synergistic therapy effect, which may find clinical applications in the future.

Disulfiram (DSF) is an effective copper (Cu 2+ )-dependent antitumor agent. In the present study, we explored use of transferrin (Tf)-modified DSF/copper sulfide (CuS) nanocomplex (Tf-DSF/CuS) for glioma therapy. Tf was used as glioma targeting motifs, DSF as an anticancer agent, and CuS as a source of Cu 2+ ions and a photothermal agent. DSF was loaded on CuS by metal-chelation, and released from the nanocomplex under acidic condition. The Tf-DSF/CuS complex exhibited high cytotoxic effect in vitro. Notably, cytotoxic activity was correlated with pH triggered release of Cu 2+ which initiated non-toxicity to toxicity switch of DSF. Ultrasound-targeted microbubble destruction (UTMD) technique was used for highly selective accumulation of intravenous injected Tf-DSF/CuS in the glioma orthotopic tumor as compared with the free drugs and non-targeted DSF/CuS groups. Magnetic resonance imaging and pathological examinations showed that Tf-DSF/CuS effectively suppressed tumor growth, with an inhibition ratio of ~85%. Additionally, DSF load did not compromise photothermal conversion ability of CuS nanoparticles. Efficacy of the photothermal ablation therapy of Tf-DSF/CuS was evaluated under 808 nm laser irradiation both in vitro and in vivo. These findings show that copper-sulfide based disulfiram nanoparticles are effective agents for anti-glioma therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Acute kidney injury (AKI) is a common pathological process that is globally associated with a high morbidity and mortality rate. The underlying AKI mechanisms include over-produced reactive oxygen species (ROS), inflammatory cell infiltration, and high levels of inflammatory mediators. Bilirubin is an endogenous compound with antioxidant, anti-inflammatory and anti-apoptotic properties, and could, therefore, be a promising therapeutic candidate. Nanotechnology-mediated therapy has emerged as a novel drug delivery strategy for AKI treatment. In this study, we report a hyaluronic acid (HA) coated ε-polylysine-bilirubin conjugate (PLBR) nanoparticle (nHA/PLBR) that can selectively accumulate in injured kidneys and alleviate the oxidative/inflammatory-induced damage. The in vitro study revealed that nHA/PLBR has good stability, biocompatibility, and exhibited higher antioxidant as well as anti-apoptotic effects when compared to nPLBR or bilirubin. The in vivo study showed that nHA/PLBR could target and accumulate in the injured kidney, effectively relieve oxidative stress and inflammatory reactions, protect the structure and function of the mitochondria, and more importantly, inhibit the apoptosis of tubular cells in an ischemia/reperfusion-induced AKI rat model. Therefore, nHA/PLBR has the capacity to enhance specific biodistribution and delivery efficiency of bilirubin, thereby providing better treatment for AKI in the future., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Surgical assailment at the vulnerable subcellular organelles (e.g. mitochondria) by photodynamic therapy (PDT) is perceived as the most devastating approach to eradicate the tumors. Herein, we programmed a novel near-infrared (NIR) PDT construct illustrating appreciable hierarchical zoom-in targeting scenario, namely, primary cell-level targeting to carcinoma post systemic dosage and subcellular level targeting to mitochondria. Pertaining to tumor-targeting function, charge reversal chemistry selectively responsive to acidic tumoral microenvironments (pH 6.8) was implemented as the external corona of PDT constructs. This charge transformative exterior entitled minimal biointerfacial reactions in systemic retention but intimate affinities to cytomembranes selectively in tumoral microenvironments, thereby resulting in preferential uptake by tumors. Furthermore, the proposed PDT constructs were equipped with mitochondria targeting triphenylphosphonium (TPP) motif, which appeared to propel intriguing 88% colocalization with mitochondria. Therefore, overwhelming cytotoxic potencies were accomplished by our carefully engineered photodynamic constructs. Another noteworthy is the photodynamic constructs characterized to be excited at tissue-penetrating NIR (980 nm) based on energy transfer between their internal components of anti-Stoke upconversion nanoparticles (UCN, donor) and photodynamic chlorin e6 (Ce6, acceptor). Therefore, practical applications for photodynamic treatment of intractable solid carcinoma were greatly facilitated and complete tumor eradication was achieved by systemic administration of the ultimate multifunctional NIR photodynamic constructs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Structure-determination methods are needed to resolve the atomic details that underlie protein function. X-ray crystallography has provided most of our knowledge of protein structure, but is constrained by the need for large, well ordered crystals and the loss of phase information. The rapidly developing methods of serial femtosecond crystallography, micro-electron diffraction and single-particle reconstruction circumvent the first of these limitations by enabling data collection from nanocrystals or purified proteins. However, the first two methods also suffer from the phase problem, while many proteins fall below the molecular-weight threshold required for single-particle reconstruction. Cryo-electron tomography of protein nanocrystals has the potential to overcome these obstacles of mainstream structure-determination methods. Here, a data-processing scheme is presented that combines routines from X-ray crystallography and new algorithms that have been developed to solve structures from tomograms of nanocrystals. This pipeline handles image-processing challenges specific to tomographic sampling of periodic specimens and is validated using simulated crystals. The tolerance of this workflow to the effects of radiation damage is also assessed. The simulations indicate a trade-off between a wider tilt range to facilitate merging data from multiple tomograms and a smaller tilt increment to improve phase accuracy. Since phase errors, but not merging errors, can be overcome with additional data sets, these results recommend distributing the dose over a wide angular range rather than using a finer sampling interval to solve the protein structure., (open access.)

Cryptosporidium is an important intestinal protozoan parasite that causes diarrhoea in humans and animals. To rapidly and specifically detect Cryptosporidium spp., we designed a pair of primers based on the small subunit ribosomal RNA (SSU rRNA) gene of Cryptosporidium spp. to be used in a new nanoparticle-assisted PCR (nano-PCR) assay. The minimum detectable concentration (1.02 pg) of this nano-PCR was 10 times more sensitive than conventional PCR using the same primer pair. The DNA samples of C. parvum, C. baileyi, C. xiaoi, C. ryanae, and C. andersoni were successfully detected by the nano-PCR. No amplifications were evident with DNA samples of some common intestinal pathogens, including Eimeria tenella, Blastocystis sp., Giardia lamblia, Enterocytozoon bieneusi, and Balantidium coli. To validate the clinical usefulness of the novel nano-PCR, a total of 40 faecal samples from goats, camels, calves, and chickens were examined. The positive rate of Cryptosporidium spp. was 27.5% (11/40), which was consistent with that of an established nested PCR. These results indicate that the novel nano-PCR assay enables the rapid, specific, and accurate detection of Cryptosporidium infection in animals. The findings provide a technical basis for the clinical diagnosis, prevention, and control of cryptosporidiosis.

Considering the high importance of the rapid detection of chloride ion (Cl - ) in sweat for the diagnosis of fibrotic cysts, we have investigated the heterogeneous halide exchange between CsPbBr 3 perovskite nanocrystals (PNCs) in n-hexane and Cl - in aqueous solution. The results show that CsPbBr 3 PNCs could achieve fast halide exchange with Cl - in the aqueous phase under magnetic stirring at pH = 1, accompanied by a significant wavelength blue shift and vivid fluorescence color changes from green to blue. Therefore, a fluorescence wavelength shift-based colorimetric sensing of Cl - based on the halide exchange of CsPbBr 3 PNCs has been developed to realize the rapid detection of Cl - in sweat. Compared with the conventional fluorescence intensity-based method, this method is of high convenience since the whole procedure could be achieved within 5 min without any sample pretreatment (even no dilution), demonstrating promising application prospects. Graphical Abstract Fluorescence wavelength-shift based colorimetric sensing of chloride in sweat via halide exchange of CsPbBr 3 perovskite nanocrystals.

Bilirubin is a yellow-colored metabolite of heme degradation (a bile pigment), once believed to be toxic, but recently recognized as a powerful endogenous antioxidant of physiologic importance. During the past two decades, several studies have demonstrated the potential of bilirubin in theranostic applications. Here this paper summarizes the current state of the field, providing a detailed review of the published literature on the theranostic applications of bilirubin-conjugated nanoparticles and the basis and mechanisms underlying their efficacy. This review covers the analytical description of the construction of the nanoparticulate bilirubin system, primary mechanisms of therapeutic action, drug delivery, and imaging potential. It also lays out the possible translational future of bilirubin-conjugated nanoparticles in therapy and diagnosis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aim of this study is to fabricate and test a 3D-printed PCL scaffold incorporating IGF-1-releasing PLGA nanoparticles for cartilage tissue engineering. IGF-1 loaded PLGA nanoparticles were produced by the double-emulsion method, and were incorporated onto 3D printed PCL scaffolds via PDA. Particle size, loading effciency (LE) and encapsulation effciency (EE) of the nanoparticles were examined. SEM, pore size, porosity, compression testing, contact angle, IGF-1 release kinetics of the composite scaffolds were also determined. For cell culture studies, CCK-8, Live/dead, MTT, GAG content and expression level of chondrocytes specific proteins and genes and HIF-1α were also tested. There was no difference of the nanoparticle size. And the LE and EE of IGF-1 in PLGA nanoparticles was about 5.53 ± 0.12% and 61.26 ± 2.71%, respectively. There was a slower, sustained release for all drug-loaded nanoparticles PLGA/PDA/PCL scaffolds. There was no difference of pore size, porosity, compressive strength of each scaffold. The contact angles PCL scaffolds were significant decreased when coated with PDA and PLGA nanoparticales. ( p  < .05) Live/dead staining showed more cells attached to the IGF-1 PLGA/PDA/PCL scaffolds. The CCK-8 and MTT assay showed higher cell proliferation and better biocompatibility of the IGF-1 PLGA/PDA/PCL scaffolds. ( p  < .05) GAG content, chondrogenic protein and gene expression level of SOX-9, COL-II, ACAN, and HIF pathway related gene (HIF-1α) were significantly higher in IGF-1 PLGA/PDA/PCL scaffolds group compared to other groups. ( p  < .05) IGF-1 PLGA/PDA/PCL scaffolds may be a better method for sustained IGF-1 administration and a promising scaffold for cartilage tissue engineering.

Targeted nanocarriers have shown great promise in drug delivery because of optimized drug behavior and improved therapeutic efficacy. How to improve the targeting efficiency of nanocarriers for the maximum possible drug delivery is a critical issue. Here we developed L-carnitine-conjugated nanoparticles targeting the carnitine transporter OCTN2 on enterocytes for improved oral absorption. As a variable, we introduced various lengths of the polyethylene glycol linker (0, 500, 1000, and 2000) between the nanoparticle surface and the ligand (CNP, C5NP, C10NP and C20NP) to improve the ligand flexibility, and consequently for more efficient interaction with the transporter, to enhance the oral delivery of the cargo load into cells. An increased absorption was observed in cellular uptake in vitro and in intestinal perfusion assay in situ when the polyethylene glycol was introduced to link L-carnitine to the nanoparticles; the highest absorption was achieved with C10NP. In contrast, the linker decreased the absorption efficiency in vivo . As the presence or absence of the mucus layer was the primary difference between in vitro / in situ versus in vivo , the presence of this layer was the likely reason for this differential effect. In summary, the size of the polyethylene glycol linker improved the absorption in vitro and in situ , but interfered with the absorption in vivo . Even though this strategy of increasing the ligand flexibility with the variable size of the polyethylene glycol failed to increase oral absorption in vivo , this approach is likely to be useful for enhanced cellular uptake following intravenous administration of the nanocarriers.

To improve synergistic anticancer efficacy and minimize the adverse effects of chemotherapeutic drugs, temozolomide (TMZ) and curcumin (CUR) co-loaded nanostructured lipid carriers (NLCs) were prepared by microemulsion in this study. And the physicochemical properties, drug release behavior, intracellular uptake efficiency, in vitro and in vivo anticancer effects of TMZ/CUR-NLCs were evaluated. TMZ/CUR-NLCs showed enhanced inhibitory effects on glioma cells compared to single drug loaded NLCs, which may be owing to that the quickly released CUR can sensitize the cancer cells to TMZ. The inhibitory mechanism is a combination of S phase cell cycle arrest associated with induced apoptosis. Notably, TMZ/CUR-NLCs can accumulate at brain and tumor sites effectively and perform a significant synergistic anticancer effect in vivo . More importantly, the toxic effects of TMZ/CUR-NLCs on major organs and normal cells at the same therapeutic dosage were not observed. In conclusion, NLCs are promising nanocarriers for delivering dual chemotherapeutic drugs sequentially, showing potentials in the synergistic treatment of tumors while reducing adverse effects both in vitro and in vivo .

Chemotherapy is one of the most potent strategies to treat gastric cancer in clinic. However, the resistance of cancer cells to chemotherapeutics is a remarkable impediment to the treatment. Moreover, signal transducer and activator of transcription 3 (STAT3) is a critical transcriptional factor that over-activated in gastric cancer, and highly involved in the induction of chemoresistance. In this study, we developed poly (lactic-co-glycolic acid) (PLGA) nanoparticles to achieve the simultaneous codelivery of doxorubicin (DOX) and nifuratel (NIF, a novel STAT3 inhibitor) for enhanced cancer therapy. The synergistic effect of DOX and NIF against cancer cells was evaluated in gastric cancer cells. PLGA nanoparticles with an optimal ratio of DOX and NIF (DNNPs) were prepared and characterized. The cellular uptake and anticancer effects of DNNPs were investigated, and the underlying mechanisms were further explored. DNNPs presented as a spherical shape, provided sustained release profiles, and exhibited significantly increased uptake and cytotoxicity in gastric cancer cells. Mechanism studies showed that DNNPs significantly induced mitochondrial-dependent apoptosis and inhibited STAT3 phosphorylation, explaining the enhanced anticancer effect. These results suggested that DNNPs represented a promising strategy against gastric cancer by inhibiting the STAT3 pathway and amplifying apoptosis., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Natural organic matter (NOM) and crystalline metal oxide nanoparticles are both prevalent in natural aquatic environments, and their interactions have important environmental and biogeochemical implications. Here, we show that these interactions are significantly affected by an intrinsic property of metal oxide nanocrystals, the exposed facets. Both anatase (TiO 2 ) and hematite (α-Fe 2 O 3 ) nanocrystals, representing common engineered and naturally occurring metal oxides, exhibited apparent facet-dependent adsorption of humic acid and fulvic acid. This facet-dependent binding was primarily driven by surface complexation between the NOM carboxyl groups and surficial metal atoms. Thus, the adsorption affinity of different-faceted nanocrystals was determined by the atomic arrangements of crystal facets that controlled the activity of metal atoms and, consequently, the ligand exchange and binding configuration of the carboxyl groups in the first hydration shell of nanocrystals. Distinct facet-dependent fractionation patterns were observed during adsorption of NOM components, particularly the low-molecular-weight and photorefractory constituents. The molecular fractionation of NOM between water and metal oxide nanoparticles was dictated by the combined effects of facet-dependent metal complexation, hydrophobic interaction, and steric hindrance and may significantly influence the NOM-driven processes occurring both in aqueous phases and at water-nanoparticle interfaces.

Experimental studies in recent years have demonstrated that the cellular uptake properties of nanoparticles can be improved by mimicking the spiky surfaces of viruses; however, little is known on how the surface topological structure of nanoparticles affects their translocation across the cell membrane. Here, by employing dissipative particle dynamics simulations, the interactions between virus-like nanoparticles (VLPs) and the lipid bilayer are investigated. The analysis of critical force for penetration demonstrates that VLPs with relatively longer and sparser spikes have better penetrability. The internalization pathway of VLPs illustrates that the spikes of VLPs can perturb the bilayer structure after VLPs adhere onto the bilayer. Furthermore, by comparing the translocation process of VLPs and spherical nanoparticles, it is found that the presence of spikes can help to increase the lateral defects in the bilayer, decrease the vertical deformation of the bilayer, and lower the density of nearby lipids during the translocation process. These effects of spikes jointly contribute to the superior penetrability of VLPs. It is expected that these findings not only enrich our understanding of how the surface topological structure affects the cellular uptake, but also pave the way for further development of VLPs for versatile biomedical applications.

Instability of silk fibroin nanoparticles (SFNPs) in physiologic condition hinders its application as drug delivery vehicle. Herein, indocyanine green (ICG) loaded silk fibroin nanoparticles (ICG-SFNPs) was firstly prepared and then crosslinked by proanthocyanidins to obtain the stable ICG-CSFNPs for killing the residual tumour niche under near infra-red irradiation (NIR) after surgery. The particle size and zeta potentials of ICG-CSFNPs was 120.1 nm and -40.4 mV, respectively. Moreover, ICG-CSFNPs exhibited good stability of particle size in the physiological medium. Meanwhile, the stable photothermal properties of ICG-CSFNPs were not compromised even after several cycles of NIR. Few of the ICG-CSFNPs were phagocytized by RAW264.7 macrophage in vitro , while they were easily internalized by C6 glioma cells, resulting in their significant toxicity on tumour cells after NIR. The pharmacokinetic study showed that ICG-CSFNPs had a longer blood circulation time than ICG-SFNPs, making them more distribution in glioma after intravenous administration in vivo . Meanwhile, the pharmacological study showed the more effective inhibition of tumour growth was exhibited by ICG-CSFNPs in C6 glioma-bearing mice after NIR. Overall, the cross-linked nanoparticles of silk fibroin may be a promising vehicle of ICG for photothermal therapy of glioma after surgical resection.

An effective steady-state redox balance is maintained in cancer cells, allowing for protection against oxidative stress and thereby enhancing cell proliferation and tumor growth. Disruption of this redox balance would increase the cellular content of reactive oxygen species (ROS) and potentiate oxidative stress-induced cell death in tumor cells, thus representing an effective strategy for cancer treatment. Glutathione (GSH) is a major reducing agent, and its cellular levels are determined at least partly by the availability of cysteine via xCT (SLC7A11)-mediated entry of cystine into cells. We developed a nanoplatform using ZnO nanoparticles (NPs) as a carrier, loaded with salicylazosulfapyridine (SASP), and stabilized with DSPE-PEG, to form ultra-small NPs (SASP/ZnO NPs). The goal of this NP strategy is to disrupt the redox balance in cells by two mechanisms: increased generation of ROS and decreased synthesis of GSH. Such an approach would be effective in killing tumor cells. As expected, the SASP/ZnO NPs enhanced ROS production because of ZnO and impaired GSH synthesis because of SASP-induced inhibition of xCT (SLC7A11) transport function. As a consequence, treatment of tumor cells with SASP/ZnO NPs in vitro and in vivo resulted in a synergistic disruptive effect on redox balance in tumor cells and induced cell death and decreased tumor growth. This ambidextrous approach has potential in cancer therapy by combining two complementary pathways to disrupt the redox balance in tumor cells.

Overcoming blood-brain barrier (BBB) and targeting tumor cells are two key steps for glioma chemotherapy. By taking advantage of the specific expression of Na + -coupled carnitine transporter 2 (OCTN2) on both brain capillary endothelial cells and glioma cells, l-carnitine conjugated poly(lactic-co-glycolic acid) nanoparticles (LC-PLGA NPs) were prepared to enable enhanced BBB permeation and glioma-cell targeting. Conjugation of l-carnitine significantly enhanced the uptake of PLGA nanoparticles in the BBB endothelial cell line hCMEC/D3 and the glioma cell line T98G. The uptake was dependent on Na + and inhibited by the excessive free l-carnitine, suggesting involvement of OCTN2 in the process. In vivo mouse studies showed that LC-PLGA NPs resulted in high accumulation in the brain as indicated by the biodistribution and imaging assays. Furthermore, compared to Taxol and paclitaxel-loaded unmodified PLGA NPs, the drug-loaded LC-PLGA NPs showed improved anti-glioma efficacy in both 2D-cell and 3D-spheroid models. The PEG spacer length of the ligand attached to the nanoparticles was optimized, and the formulation with PEG1000 (LC-1000-PLGA NPs) showed the maximum targeting efficiency. We conclude that l-carnitine-mediated cellular recognition and internalization via OCTN2 significantly facilitate the transcytosis of nanoparticles across BBB and the uptake of nanoparticles in glioma cells, resulting in improved anti-glioma efficacy.

Currently, combination drug therapy is one of the most effective approaches to glioma treatment. However, due to the inherent dissimilar pharmacokinetics of individual drugs and blood brain barriers, it was difficult for the concomitant drugs to simultaneously be delivered to glioma in an optimal dose ratio manner. Herein, a cationic micellar core (Cur-M) was first prepared from d-α-tocopherol-grafted-ε-polylysine polymer to encapsulate the hydrophobic curcumin, followed by dopamine-modified-poly-γ-glutamic acid polymer further deposited on its surface as a anion shell through pH-sensitive linkage to encapsulate the hydrophilic doxorubicin (DOX) hydrochloride. By controlling the combinational Cur/DOX molar ratio at 3:1, a pH-sensitive core-shell nanoparticle (PDCP-NP) was constructed to simultaneously target the cancer stem cells (CSCs) and the differentiated tumor cells. PDCP-NP exhibited a dynamic diameter of 160.8 nm and a zeta-potential of -30.5 mV, while its core-shell structure was further confirmed by XPS and TEM. The ratiometric delivery capability of PDCP-NP was confirmed by in vitro and in vivo studies, in comparison with the cocktail Cur/DOX solution. Meanwhile, the percentage of CSCs in tumors was significantly decreased from 4.16% to 0.95% after treatment with PDCP-NP. Overall, PDCP-NP may be a promising carrier for the combination therapy with drug candidates having dissimilar physicochemical properties.

The in vivo application of ascorbate is currently limited by the very high blood concentrations that are required to achieve therapeutic levels in tumors, which needs to exploit a novel drug platform to improve the pharmacokinetics of vitamin C (Vc) and its antitumoral effects. In this study, ascorbyl palmitate (AP), an amphiphilic molecule, is the palmitate acid ester derivative of ascorbic acid, which can be formed a "bifunctional" nanoparticle in which the AP acts not only as an antitumor drug but also as a nanocarrier for encapsulating hydrophobic antitumor drugs such as paclitaxel (PTX). We developed a bifunctional nanocarrier based on AP, which loaded with PTX for synergistic cancer chemotherapy. The resulting PTX-AP nanoparticles (PTX-APNPs) were spherical and had an average size of 294.2 nm based on dynamic light scattering. The in vitro anti-B16F10 cells test of PTX-APNPs revealed an obvious synergistic effect of AP and PTX, and the PTX-APNPs strongly induced cell apoptosis and production of reactive oxygen species. In addition, PTX-APNPs formulation also effectively suppressed the tumorigenicity of B16F10 cells in female C57BL/6 mice without causing severe toxicity. These results suggest that AP-based nanoparticles formulated with paclitaxel are useful for synergistic chemotherapy.

Introduction: Transporters in the plasma membrane have been exploited successfully for the delivery of drugs in the form of prodrugs and nanoparticles. Organic cation/carnitine transporter 2 (OCTN2, SLC22A5) has emerged as a viable target for drug delivery. OCTN2 is a Na + -dependent high-affinity transporter for L-carnitine and a Na + -independent transporter for organic cations. OCTN2 is expressed in the blood-brain barrier, heart, liver, kidney, intestinal tract and placenta and plays an essential role in L-carnitine homeostasis in the body. Areas covered: In recent years, several studies have been reported in the literature describing the utility of OCTN2 to enhance the delivery of drugs, prodrugs and nanoparticles. Here we summarize the salient features of OCTN2 in terms of its role in the cellular uptake of its physiological substrate L-carnitine in physiological and pathological context; the structural requirements for recognition and the recent advances in OCTN2-targeted drug delivery systems, including prodrugs and nanoparticles, are discussed. Expert opinion: This transporter has great potential to be utilized as a target for drug delivery to improve oral absorption of drugs in the intestinal tract. It also has potential to facilitate the transfer of drugs across the biological barriers such as the blood-brain barrier, blood-retinal barrier, and maternal-fetal barrier.

Combination therapy with different functional chemotherapeutic agents based on nano-drug delivery systems is an effective strategy for the treatment of breast cancer. However, co-delivery of drug molecules with different physicochemical properties still remains a challenge. In this study, an amphiphilic poly (ε-caprolactone)-b-poly (l-glutamic acid)-g-methoxy poly (ethylene glycol) (PCL-b-PGlu-g-mPEG) copolymer was designed and synthesized to develop a nanocarrier for the co-delivery of hydrophilic doxorubicin (DOX) and hydrophobic disulfiram (DSF). The amphiphilic copolymer self-assembled into core-shell-corona structured nanoparticles with the hydrophobic PCL core for DSF loading (hydrophobic interaction) and anionic poly (glutamic acid) shell for DOX loading (electrostatic interaction). DSF and DOX co-loaded nanoparticles (Co-NPs) resulted in high drug loading and precisely controlled DSF/DOX ratio via formulation optimization. Compared with free drug solutions, DSF and DOX delivered by the Co-NPs were found to have improved intracellular accumulation. Results of cytotoxicity assays showed that DSF/DOX delivered at the weight ratio of 0.5 and 1 could achieve a synergistic cytotoxic effect on breast cancer cell lines (MCF-7 and MDA-MB-231). In vivo imaging confirmed that the core-shell-corona nanoparticles could efficiently accumulate in tumors. In vivo anti-tumor effect results indicated that Co-NPs showed an improved drug synergistic effect on antitumor activity compared with the free drug combination. Therefore, it can be concluded that core-shell-corona nanoparticles prepared by PCL-b-PGlu-g-mPEG could be a promising co-delivery system for drug combination therapy in the treatment of breast cancer.

A co-loaded drug delivery system based on ascorbyl palmitate that can transport various functional drugs to their targets within a tumor represents an attractive strategy for increasing the efficiency of anticancer treatment. In this study, we developed a dual drug delivery system to encapsulate ascorbyl palmitate (AP) and paclitaxel (PTX) for synergistic cancer therapy. AP, which is a vitamin C derivative, and PTX were incorporated into solid lipid nanoparticles (AP/PTX-SLNs), which were used to treat murine B16F10 melanoma that had metastasized to the lungs of mice. These nanoparticles were spherical with an average size of 223 nm as measured by transmission electron microscope and dynamic light scattering. In vitro cytotoxicity assays indicated that the AP/PTX-SLNs with an AP/PTX mass ratio of 2/1 provided the optimal synergistic anticancer efficacy. In vivo, AP/PTX-SLNs were revealed to be much more effective in suppressing tumor growth in B16F10-bearing mice and in eliminating cancer cells in the lungs than single drug (AP or PTX)-loaded SLNs via a synergistic effect through reducing the Bcl-2/Bax ratio. Furthermore, no marked side effects were observed during the treatment with the AP/PTX-SLNs, indicating that the co-delivery system with ascorbyl palmitate holds promising clinical potential in cancer therapy.

l-Carnitine, obligatory for oxidation of fatty acids, is transported into cells by the Na + -coupled transporter OCTN2 and the Na + /Cl - -coupled transporter ATB 0,+ . Here we investigated the potential of L-carnitine-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) to deliver chemotherapeutic drugs into cancer cells by targeting the nanoparticles to both OCTN2 and ATB 0,+ . The cellular uptake of LC-PLGA NPs in the breast cancer cell line MCF7 and the colon cancer cell line Caco-2 was increased compared to unmodified nanoparticles, but decreased in the absence of co-transporting ions (Na + and/or Cl - ) or in the presence of competitive substrates for the two transporters. Studies with fluorescently labeled nanoparticles showed their colocalization with both OCTN2 and ATB 0,+ , confirming the involvement of both transporters in the cellular uptake of LC-PLGA NPs. As the expression levels of OCTN2 and ATB 0,+ are higher in colon cancer cells than in normal colon cells, LC-PLGA NPs can be used to deliver chemotherapeutic drugs selectively into cancer cells for colon cancer therapy. With 5-fluorouracil-loaded LC-PLGA NPs, we were able to demonstrate significant increases in the uptake efficiency and cytotoxicity in colon cancer cells that were positive for OCTN2 and ATB 0,+ . In a 3D spheroid model of tumor growth, LC-PLGA NPs showed increased uptake and enhanced antitumor efficacy. These findings indicate that dual-targeting LC-PLGA NPs to OCTN2 and ATB 0,+ has great potential to deliver chemotherapeutic drugs for colon cancer therapy. Dual targeting LC-PLGA NPs to OCTN2 and ATB0,+ can selectively deliver chemotherapeutics to colon cancer cells where both transporters are overexpressed, preventing targeting to normal cells and thus avoiding off-target side effects.

OCTN2 (SLC22A5) is a Na + -coupled absorption transporter for l-carnitine in small intestine. This study tests the potential of this transporter for oral delivery of therapeutic drugs encapsulated in l-carnitine-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) and discloses the molecular mechanism for cellular endocytosis of transporter-targeting nanoparticles. Conjugation of l-carnitine to a surface of PLGA-NPs enhances the cellular uptake and intestinal absorption of encapsulated drug. In both cases, the uptake process is dependent on cotransporting ion Na + . Computational OCTN2 docking analysis shows that the presence of Na + is important for the formation of the energetically stable intermediate complex of transporter-Na + -LC-PLGA NPs, which is also the first step in cellular endocytosis of nanoparticles. The transporter-mediated intestinal absorption of LC-PLGA NPs occurs via endocytosis/transcytosis rather than via the traditional transmembrane transport. The portal blood versus the lymphatic route is evaluated by the plasma appearance of the drug in the control and lymph duct-ligated rats. Absorption via the lymphatic system is the predominant route in the oral delivery of the NPs. In summary, LC-PLGA NPs can effectively target OCTN2 on the enterocytes for enhancing oral delivery of drugs and the critical role of cotransporting ions should be noticed in designing transporter-targeting nanoparticles., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)