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Fatty acid ethanolamides (FAEs) and endocannabinoids (ECs) have been shown to alleviate pain and inflammation, regulate motility and appetite, and produce anticancer, anxiolytic, and neuroprotective efficacies via cannabinoid receptor type 1 (CB1) or type 2 (CB2) or via peroxisome proliferator-activated receptor α (PPAR-α) stimulation. FAEs and ECs are synthesized by a series of endogenous enzymes, including N-acylphosphatidylethanolaminephospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), or phospholipase C (PLC), and their metabolism is mediated by several metabolic enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), N-acylethanolamine acid amidase (NAAA), or cyclooxygenase 2 (COX-2). Over the past decades, increasing the concentration of FAEs and ECs through the inhibition of degrading enzymes has been considered to be a viable therapeutic approach to enhance their antinociceptive and anti-inflammatory effects, as well as to protect the nervous system. [ABSTRACT FROM AUTHOR]

Poor penetration of therapeutic drugsinto tumors is a major challengein anticancer therapy, especially in solid tumors, leading to reducedtherapeutic efficacy in vivo. In the study, we used a new tumor-penetratingpeptide, CRGDK, to conjugate onto the surface of doxorubicin encapsulatednanoscale micelles. The CRGDK peptide triggered specific binding toneuropilin-1, leading to enhanced cellular uptake and cytotoxicityin vitro and highly accumulation and penetration in the tumors invivo. [ABSTRACT FROM AUTHOR]

A novel approach of ECG baseline wander correction based on mean-median filter and empirical mode decomposition is presented in this paper. The low frequency parts of the original signals were removed by the mean median filter in a nonlinear way to obtain the baseline wander estimation, then its series of IMFs were sifted by t-test after empirical mode decomposition. The proposed method, tested by the ECG signals in MIT-BIH Arrhythmia database and European ST_T database, is more effective compared with other baseline wander removal methods. [ABSTRACT FROM AUTHOR]

The importance of the unsteady effects between the casing treatment and rotor is still not clear. Experiments are conducted in a transonic compressor with arc skewed slot casing treatment configurations. The experimental results indicate that the unsteady excitation frequency due to the slot number of casing treatment is one of the most important factors influencing compressor performance. Also, compressor performance can be overall enhanced through optimizing this unsteady excitation frequency. For the transonic compressor herein, peak efficiency, stall margin, and maximum flow mass can be improved by 0.17%, 19.86%, and 0.81%, respectively, at near design rotating speed, which can reach up to 1.13%, 57.84%, and 1.57%, respectively, at part design speed. [ABSTRACT FROM AUTHOR]

Aim: The type I insulin-like growth factor receptor (IGF-IR) is overexpressed in many tumors including human hepatocellular carcinoma (HCC). It is a critical signaling molecule for tumor cell proliferation and survival. In the present study, IGF-IR expression was down-regulated by phosphorothioate antisense oligonucleotides (AS[S]ODN) to evaluate their specific effects on growth of hepatoma cells in vitro and in vivo. Methods: HepG2 cells were transfected with different doses of AS[S]ODN, sense [S]ODN, mismatch [S]ODN, or Lipofectin for 72 h, and cell proliferation was analyzed by MTS assay. In vivo, an orthotopic transplant model of HCC was established in nude mice, which were then injected with AS[S]ODN, sense [S]ODN, 5-fluorouracil or saline. At the endpoint of treatment, the tumors were excised and evaluated. Results: Compared to sense and mismatched oligonucleotides, AS[S]ODN targeting to IGF-IR mRNA significantly inhibited hepatoma cell lines HepG2 proliferation and IGF-IR expression at both mRNA and protein levels. The in vivo results showed that systemic treatment also resulted in significant inhibition in tumor growth. Tumor growth in mice treated with AS[S]ODN (50 and 75 mg/kg per day) was significantly inhibited (71.81% and 61.74%, respectively) compared to the saline-treated group ( P < 0.01) in a dose-dependent manner. The antitumor effect of IGF-IR AS[S]ODN was associated with down-regulation of IGF-IR in tumor xenografts. Furthermore, IGF-IR AS[S]ODN prevented liver recurrence tumor growth and metastasis in the lung, showing a dose-dependent response. The level of serum α-fetoprotein in AS[S]ODN-treated groups was also decreased in a dose-dependent manner, and a good correlation was observed between tumor volume and serum α-fetoprotein concentration. Conclusions: These data suggest that IGF-IR AS[S]ODN can effectively and specifically inhibit HCC growth in vitro and in vivo. Blockage of IGF-IR expression could be a promising therapeutic approach for the management of patients with HCC. [ABSTRACT FROM AUTHOR]

To evaluate thein vivoantitumor effects of Cantide and the combined effect with 5-fluorouracil.Anin situhuman hepatocellular carcinoma model was established in mice livers orthotopically. Drugs were administered intravenously and tumor sizes were monitored with calipers. Plasma alpha-fetoprotein (AFP) were detected by radiation immunoassay. Morphology of tumors was evaluated by hematoxylin-eosin (H&E) staining of histological sections. Human telomerase reverse transcriptase (hTERT) protein levels were detected by Western blotting.Cantide significantly inhibitin situhuman hepatocellular carcinoma growth in mice with a 75 and 50 mg·kg-1·d-1 administration of Cantide compared to the saline group in a dose-dependent manner, which included injecting Cantide 25 mg·kg-1·d-1-VS mg·kg-1·d-1 by iv for 20 d after surgically removing the tumor in liver. Cantide was also found to prevent tumor recurrence in the liver and metastasis in the lung, showing a dose-dependent response. When Cantide was administered by iv combined with 5-fluorouracil, it resulted in a significant reduction in tumor growth compared to either agent alone treatment group. After the treatment with Cantide alone or combined with 5-fluorouracil, plasma AFP concentration decreased in a dose-dependent manner.These results demonstrated that Cantide was an effective antitumor antisense oligonucleotidein vivoand has the potential to be developed into a clinical anti-cancer drug. [ABSTRACT FROM AUTHOR]

Municipal sludge can be utilized as a resource despite its polluting nature. However, the presence of heavy metals lowers its resource value, and their uniform dispersion in conventional biological processes because of sludge reflux poses enormous difficulties for the subsequent separation/recovery. In this study, the enrichment strategies of Cu and Zn in simulated wastewater based on a new biological process named oxic-hydrolytic & denitrification-oxic (O1/H/O2 or O/H/O) combination were investigated and the influence mechanisms of pH, chelate, operating parameters, and denitrification reaction control were illustrated. Results showed that the amount Cu and Zn in the sludge of H reactor exceeded those of both O1 and O2 when pH of O1＜6.5. The maximum sludge-water partition coefficients (K d) of Cu and Zn in H reactor were 3128 and 3421 times when the influent concentration of NH 3 –N was at a certain value (210 mg/L NH 4 Cl for Cu and 140 mg/L NH 4 Cl for Zn). This was ascribed to the control of nitrification rate, ammonification/nitrosation in the O1 reactor, anaerobic ammonia oxidation combined with autotrophic denitrification in the H reactor, optimal hydraulic retention time (HRT) and sludge retention time (SRT). Under the pre-set conditions of water quality and operation parameters, the precipitates in the sludge were found to be Cu(OH) 2 , Zn(OH) 2 , CuS, ZnS which were theoretically and instrumentally characterized. In sum, the joint regulation of biological combination and biochemical reaction will provide new enrichment/separation strategies for heavy metals in municipal sludge management. • Cu and Zn can be enriched in the H-unit sludge of a new biological process named O/H/O process. • Enrichment of Cu and Zn was the coupling of ammonization, complexation and precipitation regulated by pH. • The O/H/O process can realize the collaborative management of wastewater and sludge. [ABSTRACT FROM AUTHOR]

Due to their biodegradable character, polyesters such as polycaprolactone (PCL), poly( d , l -lactide) (PDLLA), and polylactic-co-glycolic acid (PLGA) were widely used as the hydrophobic cores of amphiphilic cationic nanoparticles (NPs) for siRNA delivery. However, fewer researches focused on facilitating siRNA delivery by adjusting the polyester composition of these nanoparticles. Herein, we investigated the contribution of polyester segments in siRNA delivery in vitro by introducing different ratio of DLLA moieties in PCL segments of mPEG-block-PCL-graft-poly(dimethylamino ethyl methacrylate)(PEG-b-PCL-g-PDMAEMA). It was noticed that compared with the other ratios of DLLA moieties, a certain molar ratio (about 70%) of the NPs, named mPEG 45 -P(CL 21 -co-DLLA 48 )-g-(PDMAEMA 29 ) 2 (PECLD-70), showed the highest gene knockdown efficiency but poorest cellular uptake ability in vitro. Further research revealed that NPs with various compositions of the polyester cores showed different physicochemical properties including particle size, zeta potential and stiffness, leading to different endocytosis mechanisms thus influencing the cellular uptake efficiency. Subsequently, we observed that the cells treated by PECLD-70 NPs/Cy5 siRNA complexes exhibited more diffuse Cy5 signal distribution than other NPs by confocal laser scanning microscope, which suggested that siRNA delivered by PECLD-70 NPs/Cy5 siRNA complexes possessed of stronger capabilities in escaping from endosome/lysosome, entering the RNA-induced silencing complex (RISC) and cutting the target mRNA efficiently. The different siRNA release profile was dominated by the degradation rate of polyester segments. Therefore, it could be concluded that the adjustment of hydrophobic core of cationic nanoparticles could significantly affect their transfection behavior and appropriate polyester composition should be concerned in designing of analogous siRNA vectors. [ABSTRACT FROM AUTHOR]

[Display omitted] • 4,7-DHC is used as a novel green photocatalyst for complete degradation of nitrobenzene; • A symbiotic reduction–oxidation process is found during the degradation; • Both reductive S 2 radicals and oxidative OH could be generated sustainably during irradiation. In this study, a synergistic reduction–oxidation process was proposed using natural organic matters (NOMs) as an organic photocatalyst for complete degradation of nitrobenzene (NB) that was difficult to oxidative decomposition directly. It has been verified by electron spin resonance (ESR) that both reductive organic free radical (4H-chromene-2,4,7-triol radical, S 2) and oxidative OH radicals could be generated sustainably by using 4,7-dihydroxycoumarin (4,7-DHC) as a green photocatalyst under UV light irradiation, and 95.07% of NB degradation efficiency was achieved after 4-h irradiation with 40 µM 4,7-DHC. The formation of aniline as a reductive product was convenient for the attack of OH radicals, making it easier for the complete degradation of NB. In addition, 4,7-DHC showed high photocatalytic activity in a wide range of pH from 1 to 13, and the best photocatalytic activity was achieved with a pH value of 4.56. Besides, the effect of common coexisted ions (SO 4 2−, Cl− and NO 3 −) on the NB degradation was discussed, and the highest k value was obtained with SO 4 2− (80 µM), NO 3 − (120 µM) or Cl− (20 µM). Moreover, 4,7-DHC exhibited extensive degradability to the frequently coexisted pollutants in NB-contaminated wastewater including humic acid (HA), aniline (AN) and m-dinitrobenzene (m-DNB), which might be extended into a potential approach for environmental remediation of NB-contaminated water due to its low cost and accessibility of 4,7-DHC as NOMs. [ABSTRACT FROM AUTHOR]

Abstract: Coating the polycation/DNA binary complexes with PEGylated polyanions can improve long-circulation and biocompatibility in vivo. However, it has been certificated PEG dilemma can reduces gene transfection efficiency because of inhibition in cellular uptake and endosomal escape. Herein, two PEGylated anionic polymers, PEGylated hyaluronic acid (HgP) and PEGylated polyglutamic acid (PGgP) were synthesized to coat the binary complexes of core–shell cationic polycaprolactone-graft-poly (N, N-dimethylaminoethyl methacrylate) nanoparticles/DNA (NP-D). The effects of polyanion structure were evaluated in terms of particle size, zeta potential, cytotoxicity, cellular uptake and transfect efficiency in vitro and in vivo. In vitro study illustrated that HgP coated complexes showed better efficiencies in both cell uptake and transfection than PGgP coated complexes. The coating of HgP on NP-D improved the biocompatibility without reduction in cell uptake and transfection efficacy, and resulted in higher accumulation and gene expression in tumor after IV injection. The success of HgP coating in overcoming PEG dilemma is attributed to the hyaluronic acid (HA)-receptor-mediated endocytosis and outer shell-detachment through the hyaluronidases catalyzed degradation of HA. These results demonstrated that HgP was a promising anionic polymer for coating the polycation/DNA complexes and ternary complexes (HgP coated NP-D) hold promising potential for cancer therapy. [Copyright &y& Elsevier]

Abstract: Small interfering RNA (siRNA) has a huge potential for the treatment or prevention of various diseases. However, to realize the therapeutic potential of siRNA drugs, efficient, tissue-specific and safe delivery technologies must be developed. Here we synthesized two kinds of polymers (PEGylated poly(2-aminoethyl methacrylate) labeled as PEG-b-PAEM or PEA, and guanidinylated PEGylated poly(2-aminoethyl methacrylate) marked as PEG-b-PAEM-co-PGEM or PEAG) using atom transfer radical polymerization and evaluated their capability of mediating siRNA delivery in vitro and in vivo. Both polymers presented excellent siRNA encapsulation ability, formed regular nanostructures with siRNA, robustly mediated cellular internalization and cytoplasmic localization of siRNA, and resulted in targeted gene knockdown efficiently. However, PEAG showed much more outstanding abilities referring to above evaluating indicators compared with PEA. Both PEA/siRNA and PEAG/siRNA polyplexes displayed strong liver, lung and spleen accumulation in mice for a long time after intravenous administration. PEAG/siApoB polyplexes (single dose at 1 mg/kg) further repressed ApoB expression in liver and resulted in block of lipid transportation. In addition, both polymers delivered high amounts of siRNA into tumor tissue in the Hela-Luc xenograft murine model. More siRNA accumulated in tumor with the increase of N/P ratio and PEAG/siRNA polyplexes showed higher siRNA accumulation than PEA/siRNA polyplexes at the same N/P ratio. These findings set the stage for further studies of structural–functional mechanisms and developments of siRNA therapeutics. [Copyright &y& Elsevier]

Abstract: Binary complexes of cationic polymers and DNA were used commonly for DNA delivery, whereas, the excess cationic charge of the binary complexes mainly leads to high toxicity and unstability in vivo. In this paper, ternary complexes by coating polyglutamic acid-graft-poly(ethylene glycol)(PGA-g-mPEG) onto binary complexes of polycaprolactone-graft-poly(N,N-dimethylaminoethyl methacrylate) (PCL-g-PDMAEMA) nanoparticles (NPs)/DNA were firstly developed for effective and targeted gene delivery. The coating of PGA-g-mPEG was able to decrease the zeta potential of the nano-sized DNA complexes nearly to electroneutrality without interferring with DNA condensation ability. As a result, the stability, the escape ability from endosomes and the transfection efficiency of the complexes were enhanced. The ternary complexes of PCL-g-PDMAEMA NPs/DNA/PGA-g-mPEG demonstrated lower cytotoxicity in CCK-8 measurements and higher gene transfection efficiency than the binary complexes in vitro. In addition, Lactate dehydrogenase (LDH) assay was performed to quantify the membrane-damaging effects of the complexes, which is consistent with the conclusion of CCK-8 measurement for cytotoxicity assay. The in vivo imaging measurement and histochemical analysis of tumor sessions confirmed that the intravenous administration of the ternary complexes with red fluorescent protein (RFP) as payload led to protein expression in tumor, which was further enhanced by the targeted coating of PGA-g-PEG-folate. [Copyright &y& Elsevier]

The Co/Ni-MOFs@CS composite derived from Co/Ni bimetallic organic framework was synthesized and characterized. Compared with a single O 3 system, the synergy between carbon sphere (CS) and metal organic frameworks (MOFs) improved the electron transfer efficiency and the formation rate of •OH. The coexistence of Co and Ni in various valence states might accelerate the cyclic process of Co(II)/Co(III) and Ni(II)/Ni(III), thereby improving the catalytic activity. Taking levofloxacin as a model pollutant, the mechanism of catalytic process was discussed, and the catalytic reaction was successfully applied to the removal of residual organics in bio-treated coking wastewater (BTCW). The removal rates of chemical oxygen demand (COD) and total organic carbon (TOC) in 60 min were 50.85%–53.71% and 39.98%–43.48%. From the perspective of UV absorption and 3D EEM, catalytic ozonation was more conducive to breaking the electronic protection of inert organic molecules such as heterocyclic compounds, and achieving higher efficiency of mineralization. It provides a new idea for catalytic ozonation technology of wastewater treatment in the future from theory, technology and application. [Display omitted] • The Co/Ni-MOFs@CS was successfully synthesized by hydrothermal method. • High specific surface areas and coexistence of multiple valence metals. • Strong nonselective oxidation capacity of OH was the mian factor for mineralization. • From the mineralization of single organic pollutant to the application of BTCW. [ABSTRACT FROM AUTHOR]

Messenger RNA (mRNA) has generated great attention due to its broad potential therapeutic applications, including vaccines, protein replacement therapy, and immunotherapy. Compared to other nucleic acids (e.g., siRNA and pDNA), there are more opportunities to improve the delivery efficacy of mRNA through systematic optimization. In this report, we studied a high-throughput library of 1200 functional polyesters for systemic mRNA delivery. We focused on the chemical investigation of hydrophobic optimization as a method to adjust mRNA polyplex stability, diameter, pKa, and efficacy. Focusing on a region of the library heatmap (PE4K-A17), we further explored the delivery of luciferase mRNA to IGROV1 ovarian cancer cells in vitro and to C57BL/6 mice in vivo following intravenous administration. PE4K-A17-0.2C8 was identified as an efficacious carrier for delivering mRNA to mouse lungs. The delivery selectivity between organs (lungs versus spleen) was found to be tunable through chemical modification of polyesters (both alkyl chain length and molar ratio in the formulation). Cre recombinase mRNA was delivered to the Lox-stop-lox tdTomato mouse model to study potential application in gene editing. Overall, we identified a series of polymer-mRNA polyplexes stabilized with Pluronic F-127 for safe and effective delivery to mouse lungs and spleens. Structure–activity relationships between alkyl side chains and in vivo delivery were elucidated, which may be informative for the continued development of polymer-based mRNA delivery. [ABSTRACT FROM AUTHOR]

The successful application of mRNA vaccines in preventing and treating infectious diseases highlights their potential as therapeutic vaccines for cancer treatment. However, unlike infectious diseases, effective antitumor therapy, particularly for solid tumors, necessitates the activation of more powerful cellular and humoral immunity to achieve clinical efficacy. Here, we report a spleen-targeted mRNA vaccine (Mn@mRNA-LNP) designed to deliver tumor antigen-encoding mRNA and manganese adjuvant (Mn 2+ ) simultaneously to dendritic cells (DCs) in the spleen. This delivery system promotes DC maturation and surface antigen presentation and stimulates the production of cytotoxic T cells. Additionally, Mn 2+ codelivered in the system serves as a safe and effective immune adjuvant, activating the stimulator of interferon genes (STING) signaling pathway and promoting the secretion of type I interferon, further enhancing the antigen-specific T cell responses. Mn@mRNA-LNP effectively inhibits tumor progression in established melanoma and colon tumor models as well as in a model of tumor recurrence after resection. Notably, the combination of Mn@mRNA-LNP with immune checkpoint inhibitors further enhances complete tumor suppression and prolonged the overall survival in mice. Overall, this "All-in-One" mRNA vaccine significantly boosts antitumor immunity responses by improving spleen targeting and immune activation, providing an attractive strategy for the future clinical translation of therapeutic mRNA vaccines.

mRNA-based applications have achieved remarkable success in the development of next-generation vaccines and the treatment of diverse liver diseases. Overcoming the challenge of delivering mRNA to extrahepatic tissues, especially specific cells within tissues, is crucial for precision therapy. In this study, a platform is developed for selective mRNA delivery to desired cells within tissues by combining lipid nanoparticle (LNP)-based targeted delivery with mRNA sequence-controlled expression. Through systematic optimization, a three-component LNP platform is developed, enabling targeted mRNA delivery to the lung, liver, and spleen. The incorporation of unique microRNA target sites into the mRNA scaffold further enhances control over protein translation in specific cells within the target tissue. This combined strategy, named SELECT (Simplified LNP with Engineered mRNA for Cell-type Targeting), demonstrates its efficacy in distinguishing mRNA expression between tumor and normal cells based on intracellular microRNA abundance. SELECT encapsulating mRNA encoding a tumor-specific cytotoxic protein, human ELANE, exhibits selective mRNA delivery to tumor lesions and significant inhibition of tumor growth in a mouse model of melanoma lung metastasis. Overall, SELECT has great potential as a new precision tumor treatment approach and also offers promising prospects for other mRNA therapies targeting specific cell types., (© 2024 Wiley‐VCH GmbH.)

Genetic medicines have the potential to treat various diseases; however, certain ailments including inflammatory diseases and cancer would benefit from control over extracellular localization of therapeutic proteins. A critical gap therefore remains the need to develop and incorporate methodologies that allow for posttranslational control over expression dynamics, localization, and stability of nucleic acid-generated protein therapeutics. To address this, we explored how the body's endogenous machinery controls protein localization through signal peptides (SPs), including how these motifs could be incorporated modularly into therapeutics. SPs serve as a virtual zip code for mRNA transcripts that direct the cell where to send completed proteins within the cell and the body. Utilizing this signaling biology, we incorporated secretory SP sequences upstream of mRNA transcripts coding for reporter, natural, and therapeutic proteins to induce secretion of the proteins into systemic circulation. SP sequences generated secretion of various engineered proteins into the bloodstream following intravenous, intramuscular, and subcutaneous SP mRNA delivery by lipid, polymer, and ionizable phospholipid delivery carriers. SP-engineered etanercept/TNF-α inhibitor proteins demonstrated therapeutic efficacy in an imiquimod-induced psoriasis model by reducing hyperkeratosis and inflammation. An SP-engineered anti-PD-L1 construct mediated mRNA encoded proteins with longer serum half-lives that reduced tumor burden and extended survival in MC38 and B16F10 cancer models. The modular nature of SP platform should enable intracellular and extracellular localization control of various functional proteins for diverse therapeutic applications., Competing Interests: Competing interests statement:D.J.S. is on the scientific advisory boards of ReCode Therapeutics and Tome Biosciences. D.J.S. owns stock or stock options in Signify Bio, ReCode Therapeutics, and Tome Biosciences. L.F. owns stock in Signify Bio. The University of Texas System has filed patent applications related to the described technology. L.F. and D.J.S. are co-founders of Signify Bio, which has licensed intellectual property from UT Southwestern.

Messenger RNA (mRNA) has received great attention in the prevention and treatment of various diseases due to the success of coronavirus disease 2019 (COVID-19) mRNA vaccines (Comirnaty and Spikevax). To meet the therapeutic purpose, it is required that mRNA must enter the target cells and express sufficient proteins. Therefore, the development of effective delivery systems is necessary and crucial. Lipid nanoparticle (LNP) represents a remarkable vehicle that has indeed accelerated mRNA applications in humans, as several mRNA-based therapies have already been approved or are in clinical trials. In this review, the focus is on mRNA-LNP-mediated anticancer therapy. It summarizes the main development strategies of mRNA-LNP formulations, discusses representative therapeutic approaches in cancer, and points out current challenges and possible future directions of this research field. It is hoped that these delivered messages can help further improve the application of mRNA-LNP technology in cancer therapy., (© 2023 Wiley-VCH GmbH.)

Approximately 10% of Cystic Fibrosis (CF) patients, particularly those with CF transmembrane conductance regulator (CFTR) gene nonsense mutations, lack effective treatments. The potential of gene correction therapy through delivery of the CRISPR/Cas system to CF-relevant organs/cells is hindered by the lack of efficient genome editor delivery carriers. Herein, we report improved Lung Selective Organ Targeting Lipid Nanoparticles (SORT LNPs) for efficient delivery of Cas9 mRNA, sgRNA, and donor ssDNA templates, enabling precise homology-directed repair-mediated gene correction in CF models. Optimized Lung SORT LNPs deliver mRNA to lung basal cells in Ai9 reporter mice. SORT LNP treatment successfully corrected the CFTR mutations in homozygous G542X mice and in patient-derived human bronchial epithelial cells with homozygous F508del mutations, leading to the restoration of CFTR protein expression and chloride transport function. This proof-of-concept study will contribute to accelerating the clinical development of mRNA LNPs for CF treatment through CRISPR/Cas gene correction., (© 2023. The Author(s).)

Harnessing surface engineering strategies to functionalize nucleic acid-lipid nanoparticles (LNPs) for improved performance has been a hot research topic since the approval of the first siRNA drug, patisiran, and two mRNA-based COVID-19 vaccines, BNT162b2 and mRNA-1273. Currently, efforts have been mainly made to construct targeted LNPs for organ- or cell-type-specific delivery of nucleic acid drugs by conjugation with various types of ligands. In this review, we describe the surface engineering strategies for nucleic acid-LNPs, considering ligand types, conjugation chemistries, and incorporation methods. We then outline the general purification and characterization techniques that are frequently used following the engineering step and emphasize the specific techniques for certain types of ligands. Next, we comprehensively summarize the currently accessible organs and cell types, as well as the other applications of the engineered LNPs. Finally, we provide considerations for formulating targeted LNPs and discuss the challenges of successfully translating the "proof of concept" from the laboratory into the clinic. We believe that addressing these challenges could accelerate the development of surface-engineered LNPs for targeted nucleic acid delivery and beyond., Competing Interests: Yi Lin, Qiang Cheng and Tuo Wei declare that they have no conflict of interest., (© The Author(s) 2023.)

Due to the phosphorus (P) deficiency in coking wastewater, sufficient P needs to be provided in the treatment process to maintain biotic activity. However, most of the dosed P sources are transferred to the sludge phase out of the chemical equilibrium. After an in-depth investigation of P morphology changes in coking wastewater treatment, it is found that above 71.6 % P applied to the full-scale O/H/H/O (oxic-hydrolytic & denitrification-hydrolytic & denitrification-oxic) process for coking wastewater treatment is ended up in the sludge phase of the aerobic reactors in the forms of non-apatite inorganic phosphorus (NAIP). Theoretical simulations suggest that the P forms precipitates such as FePO 4 ·2H 2 O, AlPO 4 ·2H 2 O, MnHPO 4 at pH < 7, and Ca 5 (PO 4 ) 3 OH at pH > 7. Microbial utilization of P in coking wastewater treatment is swayed by precipitation, pH and sludge retention time (SRT). By pyrolysis treatment of the waste sludge at 700 °C, phosphoric substances in coking sludge are enriched and converted into Ca 5 (PO 4 ) 3 OH, Ca 5 (PO 4 ) 3 Cl, Ca 3 (PO 4 ) 2 , etc. with apatite phosphorus (AP) accounting for 65.7 % of total phosphorus. Moreover, the heavy metals in biochar were below the national standard limits for discharge. This study shows that hazardous waste (coking sludge) can be transformed into bioavailable products (P-rich biochar) through comprehensive management of the fate of P. Combined with the O/H/H/O process, the mechanisms of phosphorus consumption in coking wastewater treatment are revealed for the first time, which will facilitate a reduced consumption of phosphorus and provide a demonstration for other phosphorus-deficient industrial wastewater treatment., Competing Interests: Declaration of competing interest We declare that the manuscript consists of original and unpublished work, which is not under consideration for publication elsewhere, in whole or in part. The manuscript is approved by all authors for publication. No conflict of interest presents in the submission of this manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Hydraulic retention time (HRT), as an important parameter in the wastewater treatment process, has a great impact on water quality and energy consumption. With the rapid advances in computer technology and deepened understanding of in microbial metabolism, a series of activated sludge models (ASMs) have been developed and applied in wastewater treatment. However, ASMs simulation based on the nexus of HRT, water treatment process, water quality and energy consumption has yet to be verified. In this study, HRT was creatively linked to water treatment process variation. And a novel combined process model (CPM) was developed based on the operational data and treatment performance data from 4 full-scale coking wastewater treatment processes. In the CPM, an array of biological treatment processes were represented by setting the HRT in respective treatment units of the anaerobic-oxic-hydrolytic & denitrification-oxic (A/O/H/O) process. The relationships between HRT, effluent quality and energy consumption were systematically analyzed. Results showed that: (i) for A/O/H/O process, the HRT of first oxic (O1) reactor has a key effect on the effluent water quality and energy consumption, while the impact of the anaerobic (A) reactor HRT was limited; (ii) the O/H/O process has a clear advantage in treating coking wastewater due to the carbon removal and detoxification function of O1 reactor; (iii) the lowest energy consumption (with the total system HRT below 210 h) to meet the biological effluent quality requirements (COD = 200 mg/L, TN = 50 mg/L) is 4.429 kWh/m 3 . Since the CPM could effectively work out the optimal process configuration and break the boundaries between HRT and process variation, it has enormous potential to be extended to the design of other wastewater treatment processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Germline or somatic loss-of-function mutations of fumarate hydratase (FH) predispose patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection there is no effective therapy for metastatic FH-deficient RCC, an accurate method for early diagnosis is needed. Although MRI or CT scans are offered, they cannot differentiate FH-deficient tumors from other RCCs. Therefore, finding noninvasive plasma biomarkers suitable for rapid diagnosis, screening, and surveillance would improve clinical outcomes. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed plasma metabolomics analysis and identified 2 tumor-derived metabolites, succinyl-adenosine and succinic-cysteine, as excellent plasma biomarkers for early diagnosis. These 2 molecules reliably reflected the FH mutation status and tumor mass. We further identified the enzymatic cooperativity by which these biomarkers are produced within the tumor microenvironment. Longitudinal monitoring of patients demonstrated that these circulating biomarkers can be used for reporting on treatment efficacy and identifying recurrent or metastatic tumors.

How N 6 -methyladenosine (m 6 A), the most abundant mRNA modification, contributes to primate tissue homeostasis and physiological aging remains elusive. Here, we characterize the m 6 A epitranscriptome across the liver, heart and skeletal muscle in young and old nonhuman primates. Our data reveal a positive correlation between m 6 A modifications and gene expression homeostasis across tissues as well as tissue-type-specific aging-associated m 6 A dynamics. Among these tissues, skeletal muscle is the most susceptible to m 6 A loss in aging and shows a reduction in the m 6 A methyltransferase METTL3. We further show that METTL3 deficiency in human pluripotent stem cell-derived myotubes leads to senescence and apoptosis, and identify NPNT as a key element downstream of METTL3 involved in myotube homeostasis, whose expression and m 6 A levels are both decreased in senescent myotubes. Our study provides a resource for elucidating m 6 A-mediated mechanisms of tissue aging and reveals a METTL3-m 6 A-NPNT axis counteracting aging-associated skeletal muscle degeneration., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)