Charge barriers in the kidney elimination of engineered nanoparticles.

The renal elimination pathway is increasingly harnessed to reduce nonspecific accumulation of engineered nanoparticles within the body and expedite their clinical applications. While the size of nanoparticles is recognized as crucial for their passive filtration through the glomerulus due to its limited pore size, the influence of nanoparticle charge on their transport and interactions within the kidneys remains largely elusive. Herein, we report that the proximal tubule and peritubular capillary, rather than the glomerulus, serve as primary charge barriers to the transport of charged nanoparticles within the kidney. Employing a series of ultrasmall, renal-clearable gold nanoparticles (AuNPs) with precisely engineered surface charge characteristics as multimodal imaging agents, we have tracked their distribution and retention across various kidney components following intravenous administration. Our results reveal that retention in the proximal tubules is governed not by the nanoparticle's zeta-potential, but by direct Coulombic interactions between the positively charged surface ligands of the AuNPs and the negatively charged microvilli of proximal tubules. However, further enhancing these interactions leads to increased binding of the positively charged AuNPs to the peritubular capillaries during the initial phase of elimination, subsequently facilitating their slow passage through the glomeruli and interaction with tubular components in a charge-selective manner. By identifying these two critical charge-dependent barriers in the renal transport of nanoparticles, our findings offer a fundamental insight for the design of renal nanomedicines tailored for selective targeting within the kidney, laying down a foundation for developing targeting renal nanomedicines for future kidney disease management in the clinics.

Physiological principles underlying the kidney targeting of renal nanomedicines.

Kidney disease affects more than 10% of the global population and is associated with considerable morbidity and mortality, highlighting a need for new therapeutic options. Engineered nanoparticles for the treatment of kidney diseases (renal nanomedicines) represent one such option, enabling the delivery of targeted therapeutics to specific regions of the kidney. Although they are underdeveloped compared with nanomedicines for diseases such as cancer, findings from preclinical studies suggest that renal nanomedicines may hold promise. However, the physiological principles that govern the in vivo transport and interactions of renal nanomedicines differ from those of cancer nanomedicines, and thus a comprehensive understanding of these principles is needed to design nanomedicines that effectively and specifically target the kidney while ensuring biosafety in their future clinical translation. Herein, we summarize the current understanding of factors that influence the glomerular filtration, tubular uptake, tubular secretion and extrusion of nanoparticles, including size and charge dependency, and the role of specific transporters and processes such as endocytosis. We also describe how the transport and uptake of nanoparticles is altered by kidney disease and discuss strategic approaches by which nanoparticles may be harnessed for the detection and treatment of a variety of kidney diseases.

A Triptycene-Based Layered/Flower-Like 2D Conductive Metal-Organic Framework with 3D Extension as an Electrode for Efficient Li Storage.

2D metal-organic frameworks (2D MOFs) with π conjugation have attracted widespread attention in the field of lithium storage due to their unique electron transfer units and structural characteristics. However, the periodic 2D planar extension structure hides some active sites, which is not conducive to the utilization of its structural advantages. In this work, a series of triptycene-based 2D conductive MOFs (M-DBH, M = Ni, Mn, and Co) with 3D extension structures are constructed by coordinating 9,10-dihydro-9,10-[1,2]benzenoanthracene-2,3,6,7,14,15-hexaol with metal ions to explore their potential applications in lithium-ion and lithium-sulfur batteries. This is the first study in which 2D conductive MOFs with the 3D extended molecule are used as electrode materials for lithium storage. The designed material generates rich active sites through staggered stacking layers and shows excellent performance in lithium-ion and lithium-sulfur batteries. The capacity retention rate of Ni-DBH can reach over 70% after 500 cycles at 0.2 C in lithium-ion batteries, while the capacity of S@Mn-DBH exceeds 305 mAh g-1 after 480 cycles at 0.5 C in lithium-sulfur batteries. Compared with the materials with 2D planar extended structures, the M-DBH electrodes with 3D extended structures in this work exhibit better performance in terms of cycle time and lithium storage capacity.

Crosstalk between Hepatic Glutathione Efflux and Tumor Targeting Efficiency of Indocyanine Green-Conjugated Gold Nanoparticles.

The elevated glutathione (GSH) level in solid tumors has been used as a major hallmark for GSH-responsive nanoparticles to enhance targeting efficiency and specificity. Meanwhile, GSH is mainly synthesized inside the hepatocytes of the liver in the body and constantly released into the blood through hepatic GSH efflux to regulate redox potential of the entire body. However, it remains largely unknown how this hepatic GSH efflux affects the tumor targeting of GSH-responsive nanoparticles. Herein, we report that depletion of hepatic GSH enhanced the tumor targeting of GSH-responsive indocyanine green-conjugated Au25 nanoclusters coated with 18 GSH ligand (ICG-Au25 SG18 ). The dissociation of ICG from Au25 SG18 by the hepatic GSH through thiol-exchange reaction and the subsequent hepatobiliary clearance of the detached ICG were slowed down by GSH depletion, which in turn prolonged the blood circulation of intact ICG-Au25 SG18 and enhanced its tumor targeting. Our work highlights glutathione-mediated crosstalk between the liver and tumor, in addition to well-known Kupffer cell-mediated uptake, in the tumor targeting of engineered nanoparticles, which could be modulated to enhance targeting efficiency and specificity of cancer nanomedicines while reducing their nonspecific accumulation.

The early Cambrian Kylinxia zhangi and evolution of the arthropod head.

The early Cambrian Kylinxia zhangi occupies a pivotal position in arthropod evolution, branching from the euarthropod stem lineage between radiodonts (Anomalocaris and relatives) and "great-appendage" arthropods.1,2 Its combination of appendage and exoskeletal features is viewed as uniquely bridging the morphologies of so-called "lower" and "upper" stem-group euarthropods.3,4 Microtomographic study of new specimens of Kylinxia refines and corrects previous interpretation of head structures in this species. Phylogenetic analyses incorporating new data reinforce the placement of Kylinxia in the euarthropod stem group but support new hypotheses of head evolution. The head of Kylinxia is composed of six segments, as in extant mandibulates, e.g., insects.5 In Kylinxia, these are an anterior sclerite associated with an unpaired median eye and paired lateral eyes (thus three rather than five eyes as was previously described1), deutocerebral frontal-most appendages, and four pairs of biramous appendages (rather than two pairs of uniramous appendages). Phylogenetic trees suggest that a six-segmented head in the euarthropod crown group was already acquired by a common ancestor with Kylinxia. The segmental alignment and homology of spinose frontal-most appendages between radiodonts and upper stem-group euarthropods6,7,8,9,10 is bolstered by morphological similarities and inferred phylogenetic continuity between Kylinxia and other stem-group euarthropods.

Proximal tubules eliminate endocytosed gold nanoparticles through an organelle-extrusion-mediated self-renewal mechanism.

Proximal tubules energetically internalize and metabolize solutes filtered through glomeruli but are constantly challenged by foreign substances during the lifespan. Thus, it is critical to understand how proximal tubules stay healthy. Here we report a previously unrecognized mechanism of mitotically quiescent proximal tubular epithelial cells for eliminating gold nanoparticles that were endocytosed and even partially transformed into large nanoassemblies inside lysosomes/endosomes. By squeezing ~5 µm balloon-like extrusions through dense microvilli, transporting intact gold-containing endocytic vesicles into the extrusions along with mitochondria or other organelles and pinching the extrusions off the membranes into the lumen, proximal tubular epithelial cells re-eliminated >95% of endocytosed gold nanoparticles from the kidneys into the urine within a month. While this organelle-extrusion mechanism represents a new nanoparticle-elimination route, it is not activated by the gold nanoparticles but is an intrinsic 'housekeeping' function of normal proximal tubular epithelial cells, used to remove unwanted cytoplasmic contents and self-renew intracellular organelles without cell division to maintain homoeostasis.

Vertical differentiation of soil organic carbon in mature natural forests in China.

We analyzed the effects of meteorological factors and soil properties on vertical variation of SOC, based on soil organic carbon (SOC) density in different soil layers (0-10, 10-20, 20-30, 30-50, and 50-100 cm) from 131 mature natural forests in different climate zones in China. The results showed that SOC density decreased with increasing soil depth (0-30 cm) in temperate coniferous, temperate deciduous broadleaved, subtropical deciduous broadleaved and subtropical evergreen broadleaved forests. There were significant regional variations of SOC density in 0-100 cm soil layer. SOC density of 0-100 cm soil layer in temperate coniferous forests was higher than temperate deciduous broadleaved forests, and was higher in subtropical evergreen broadleaved forests than subtropical deciduous broadleaved forests. SOC density was significantly positively correlated with soil clay content, mean annual precipitation, and aboveground net primary production, and significantly negatively correlated with soil pH and mean annual temperature. Mean annual precipitation and mean annual temperature influenced input and output of SOC, while soil pH and clay content affected SOC accumulation. Therefore, protecting mature natural coniferous and evergreen broadleaved forests would benefit forest carbon sequestration in China.

[Effects of simulated acid rain on soil N2O emission from typical forest in subtropical sou-thern China.] / æ¨¡æ‹Ÿé ¸é›¨å¯¹å—äºšçƒ­å¸¦å ¸åž‹æ£®æž—åœŸå£¤N2O排放的影响.

Based on a long-term simulated acid rain experiment, soil N2O emission fluxes were measured using static chambers and the gas chromatography method in a coniferous and broadleaved mixed forest and a monsoon evergreen broadleaved forest in southern China. During the five-year observation periods (2014-2018), soil N2O emission fluxes in the two forests showed obvious seasonal variation. The soil N2O emission fluxes in wet season were significantly higher than that in dry season, with a large annual variation. Due to the decreases of precipitation, soil N2O emission fluxes of the two forests in 2017 and 2018 were generally low. Soil N2O emission flux was positively correlated with soil temperature and soil moisture. In the monsoon evergreen broadleaved forest, soil N2O emission flux in the control plot was 12.6 µg N2O·m-2·h-1. Soil N2O emission fluxes under the pH 3.5 and pH 3.0 treatments increased by 42.9% and 61.1%, respectively. Soil N2O emission was significantly increased under simulated acid rain in the monsoon evergreen broadleaved forest. Acid rain promoted soil N2O emission in the coniferous and broadleaved mixed forest, but without significant difference among the treatments. Under the scenario of increasing acid rain, soil N2O emission fluxes in typical subtropical southern China forests would increase, and the magnitude of such increase was different among forest types.

Noninvasive monitoring of hepatic glutathione depletion through fluorescence imaging and blood testing.

Hepatic glutathione plays a key role in regulating redox potential of the entire body, and its depletion is known to increase susceptibility to oxidative stress involved in many diseases. However, this crucial pathophysiological event can only be detected noninvasively with high-end instrumentation or invasively with surgical biopsy, limiting both preclinical research and clinical prevention of oxidative stress-related diseases. Here, we report that both in vivo fluorescence imaging and blood testing (the first-line detection in the clinics) can be used for noninvasive and consecutive monitoring of hepatic glutathione depletion at high specificity and accuracy with assistance of a body-clearable nanoprobe, of which emission and surface chemistries are selectively activated and transformed by hepatic glutathione in the liver sinusoids. These findings open a new avenue to designing exogenous blood markers that can carry information of local disease through specific nanobiochemical interactions back to the bloodstream for facile and rapid disease detection.

Hyperfluorescence Imaging of Kidney Cancer Enabled by Renal Secretion Pathway Dependent Efflux Transport.

Renal tubular secretion is an active efflux pathway for the kidneys to remove molecules but has yet to be used to enhance kidney cancer targeting. We report indocyanine green (ICG) conjugated with a 2100 Da PEG molecule (ICG-PEG45) as a renal-tubule-secreted near-infrared-emitting fluorophore for hyperfluorescence imaging of kidney cancers, which cannot be achieved with hepatobiliary- and glomerular-clearable ICG. This pathway-dependent targeting of kidney cancer arises from the fact that the secretion pathway enables ICG-PEG45 to be effectively effluxed out of normal proximal tubules through P-glycoprotein transporter while being retained in cancerous kidney tissues with low P-glycoprotein expression. Tuning elimination pathways and utilizing different efflux kinetics of medical agents in normal and diseased tissues could be a new strategy for tackling challenges in disease diagnosis and treatments that cannot be addressed with passive and ligand-receptor-mediated active targeting.

The response of soil respiration to precipitation change is asymmetric and differs between grasslands and forests.

Intensification of the Earth's hydrological cycle amplifies the interannual variability of precipitation, which will significantly impact the terrestrial carbon (C) cycle. However, it is still unknown whether previously observed relationship between soil respiration (Rs ) and precipitation remains applicable under extreme precipitation change. By analyzing the observations from a much larger dataset of field experiments (248 published papers including 151 grassland studies and 97 forest studies) across a wider range of precipitation manipulation than previous studies, we found that the relationship of Rs response with precipitation change was highly nonlinear or asymmetric, and differed significantly between grasslands and forests, between moderate and extreme precipitation changes. Response of Rs to precipitation change was negatively asymmetric (concave-down) in grasslands, and double-asymmetric in forests with a positive asymmetry (concave-up) under moderate precipitation changes and a negative asymmetry (concave-down) under extreme precipitation changes. In grasslands, the negative asymmetry in Rs response was attributed to the higher sensitivities of soil moisture, microbial and root activities to decreased precipitation (DPPT) than to increased precipitation (IPPT). In forests, the positive asymmetry was predominantly driven by the significant increase in microbial respiration under moderate IPPT, while the negative asymmetry was caused by the reductions in root biomass and respiration under extreme DPPT. The different asymmetric responses of Rs between grasslands and forests will greatly improve our ability to forecast the C cycle consequences of increased precipitation variability. Specifically, the negative asymmetry of Rs response under extreme precipitation change suggests that the soil C efflux will decrease across grasslands and forests under future precipitation regime with more wet and dry extremes.

Cancer Photothermal Therapy with ICG-Conjugated Gold Nanoclusters.

The coming era of precision nanomedicine demands engineered nanoparticles that can be readily translated into the clinic, like that of molecular agents, without being hindered by intrinsic size heterogeneity and long-term body retention. Herein we report that conjugation of indocyanine green (ICG), an FDA-approved near-infrared (NIR) dye, onto an atomically precise glutathione-coated Au25 (GS-Au25) nanocluster led to a molecular-like photothermal nanoparticle (ICG4-GS-Au25) with significantly enhanced ICG photostability and tumor targeting. Under weak NIR light irradiation conditions, free ICG failed to suppress tumor growth but the original tumors were completely eradicated with ICG4-GS-Au25. In the meantime, "off-target" ICG4-GS-Au25 was effectively cleared out from the body like small-molecule drugs after glutathione-mediated biotransformation in the liver. These findings highlight the merits of molecular-like nanomedicines, offering a new pathway to meet FDA's criteria for the clinical translation of nanomedicines.

In Situ Ligand-Directed Growth of Gold Nanoparticles in Biological Tissues.

Fundamental understandings and precise control of nanoparticle growth in the complex biological environment are crucial to broadening their potential applications in tissue imaging. Herein, we report that glutathione (GSH), a widely used capping ligand for precise control of the size of gold nanoparticle (AuNP) down to single-atom level in test tubes, can also be used to direct the selective growth of the AuNPs in the mitochondria of renal tubule cells as well as hippocampus cells in the tissues. Precise control of this growth process can lead to the formation of both ultrasmall AuNPs with near-infrared luminescence and large plasmonic AuNPs. The observed selective growth of the AuNPs is likely due to unique GSH storage function of the mitochondria. Using a different ligand, ß-glucose thiol, we also found that the brush border of the intestine for glucose absorption became the major site for the growth of luminescent AuNPs. These findings suggest that selective growth of AuNPs in the biological tissues can indeed be directed with specific ligands, opening up a new avenue to tissue labeling and future development of artificial bionano hybrid systems.

Divergent responses of soil organic carbon accumulation to 14 years of nitrogen addition in two typical subtropical forests.

Developing an understanding of the response of soil organic carbon (SOC) to N addition is critical to quantify and predict the terrestrial carbon uptake under increasing N deposition in the future. However, results from field studies on the response of SOC content and composition to N addition are highly variable across different ecosystems. The interpretation of SOC responses to N addition are often complicated by the differences in climate, soil substrate and other factors. To address this question, we measured SOC and its components in adjacent broadleaved and coniferous subtropical forests after 14 years of N addition. SOC in the top 50 cm increased by 2.1 kg m-2, 1.8 kg m-2 and 1.2 kg m-2 for low, medium and high rates of N addition in the broadleaved forest, but did not change significantly in the coniferous forest. Increased SOC in the broadleaved forest was contributed by the significant increases in particulate organic carbon (POC), humus organic carbon (HOC) in the 0-10 cm and 30-50 cm soil layers and resistant organic carbon (ROC) in the 0-10 cm soil layer. 13C nuclear magnetic resonance (NMR) spectra of coarse SOC revealed a decrease in easily decomposed carbon (C) and a shift in recalcitrant C. The increased SOC accumulation in the broadleaved forest was largely driven by altered rates of organic matter decomposition, rather than C inputs to soil. Land-history and low nutrient availability may have contributed to the lack of significant impact of N addition on SOC in the coniferous forest. Our results suggested the different controls of SOC accumulation and less sensitivity of SOC chemical composition at the molecular level to N addition in the two subtropical forest soils.

Tailoring Kidney Transport of Organic Dyes with Low-Molecular-Weight PEGylation.

Subtle changes in size can induce distinct responses of the body to hard nanomaterials; however, it is largely unknown whether just a few ethylene oxide unit differences in soft poly(ethylene glycol) (PEG) molecules could significantly alter the renal clearance of small molecules. By systematically investigating in vivo transport of the representative renal clearable organic dyes, IRDye800CW after being conjugated with a series of PEG molecules with molecular weight (MW) below 10 kDa, we found a MW-dependent scaling law: PEG45 (MW = 2100 Da) is an optimized MW to generate the most efficient renal clearance for IRDye800CW by expediting the glomerular filtration of organic dyes and reducing their nonspecific interactions with background tissue. Moreover, the uniqueness of PEG45 can be generalized to other organic dyes such as ZW800-1 and fluorescein. This finding highlights the importance of low-MW PEGylation in tailoring in vivo transport of organic fluorophores, which would broaden their biomedical applications.

Correlating Anticancer Drug Delivery Efficiency with Vascular Permeability of Renal Clearable Versus Non-renal Clearable Nanocarriers.

Enhancing tumor targeting of nanocarriers has been a major strategy for advancing clinical translation of cancer nanomedicines. Herein, we report a head-to-head comparison between 5 nm renal clearable and 30 nm non-renal clearable gold nanoparticle (AuNP)-based drug delivery systems (DDSs) in the delivery of doxorubicin (DOX). While the two DDSs themselves had comparable tumor targeting, we found their different vascular permeability played an even more important role than blood retention in the delivery and intratumoral transport of DOX, of which tumor accumulation, efficacy, and therapeutic index were enhanced 2, 7, and 10-fold, respectively, for the 5 nm DDS over 30 nm one. These findings indicate that ultrahigh vascular permeability of renal clearable nanocarriers can be utilized to further improve anticancer drug delivery without the need for prolonged blood retention.

Tuning the In†Vivo Transport of Anticancer Drugs Using Renal-Clearable Gold Nanoparticles.

Precise control of in vivo transport of anticancer drugs in normal and cancerous tissues with engineered nanoparticles is key to the future success of cancer nanomedicines in clinics. This requires a fundamental understanding of how engineered nanoparticles impact the targeting-clearance and permeation-retention paradoxes in the anticancer-drug delivery. Herein, we systematically investigated how renal-clearable gold nanoparticles (AuNPs) affect the permeation, distribution, and retention of the anticancer drug doxorubicin in both cancerous and normal tissues. Renal-clearable AuNPs retain the advantages of the free drug, including rapid tumor targeting and high tumor vascular permeability. The renal-clearable AuNPs also accelerated body clearance of off-target drug via renal elimination. These results clearly indicate that diverse in vivo transport behaviors of engineered nanoparticles can be used to reconcile long-standing paradoxes in the anticancer drug delivery.

Renal Clearable Luminescent Gold Nanoparticles: From the Bench to the Clinic.

With more and more engineered nanoparticles (NPs) being translated to the clinic, the United States Food and Drug Administration (FDA) has recently issued the latest draft guidance on nanomaterial-containing drug products with an emphasis on understanding their in vivo transport and nano-bio interactions. Following these guidelines, NPs can be designed to target and treat diseases more efficiently than small molecules, have minimum accumulation in normal tissues, and induce minimum toxicity. In this Minireview, we integrate this guidance with our ten-year studies on developing renal clearable luminescent gold NPs. These gold NPs resist serum protein adsorption, escape liver uptake, target cancerous tissues, and report kidney dysfunction at early stages. At the same time, off-target gold NPs can be eliminated by the kidneys with minimum accumulation in the body. Additionally, we identify challenges to the translation of renal clearable gold NPs from the bench to the clinic.

How nanotechnology imaging can be used in kidney disease: an interview with Dr Mengxiao Yu.

Author biography Dr Yu currently is a research assistant professor at University of Texas at Dallas and is the Chief Scientist and Chief Executive Officer of ClearNano, Inc. She received her B.S. in Chemistry from Beijing Normal University in China in 2004, and her PhD in Chemistry from Fudan University in 2009. After that she joined Dr Jie Zheng's group at University of Texas at Dallas as a postdoctoral fellow and was promoted to research scientist in 2014 and research assistant professor in 2015. Her current research area comprises renal nanomedicine, biomedical imaging, luminescent gold nanoparticles and kidney disease detection.

Effect of Hydrophobicity on Nano-Bio Interactions of Zwitterionic Luminescent Gold Nanoparticles at the Cellular Level.

Fundamental understanding of how the hydrophobicity impacts cellular interactions of engineered nanoparticles is critical to their future success in healthcare. Herein, we report that inserting hydrophobic octanethiol onto the surface of zwitterionic luminescent glutathione coated gold nanoparticles (GS-AuNPs) of 2 nm enhanced their affinity to the cellular membrane and increased cellular uptake kinetics by more than one order of magnitude, rather than inducing the accumulation of the AuNPs in the bilayer core or enhancing their passive diffusion. These studies highlight the diversity and heterogeneity in the hydrophobicity-induced nano-bio interactions at the cellular level and offer a new pathway to expediting cellular uptake of engineered nanoparticles. In addition, the amphiphilic luminescent AuNPs with high affinity to cell membrane and rapid endocytosis potentially serve as dual-modality imaging probes to correlate fluorescence and electron microscopies at the cellular level.