Neuronal double-stranded DNA accumulation induced by DNase II deficiency drives tau phosphorylation and neurodegeneration.

BACKGROUND: Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer's disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified. METHODS: The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test. RESULTS: The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits. CONCLUSIONS: DNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders.

Ionic Photovoltaics-in-Memory in van der Waals Material.

The photovoltaic effect is gaining growing attention in the optoelectronics field due to its low power consumption, sustainable nature, and high efficiency. However, the photovoltaic effects hitherto reported are hindered by the stringent band-alignment requirement or inversion symmetry-breaking, and are challenging for achieving multifunctional photovoltaic properties (such as reconfiguration, nonvolatility, and so on). Here, a novel ionic photovoltaic effect in centrosymmetric CdSb2Se3Br2 that can overcome these limitations is demonstrated. The photovoltaic effect displays significant anisotropy, with the photocurrent being most apparent along the CdBr2 chains while absent perpendicular to them. Additionally, the device shows electrically-induced nonvolatile photocurrent switching characteristics. The photovoltaic effect is attributed to the modulation of the built-in electric field through the migration of Br ions. Using these unique photovoltaic properties, a highly secure circuit with electrical and optical keys is successfully implemented. The findings not only broaden the understanding of the photovoltaic mechanism, but also provide a new material platform for the development of in-memory sensing and computing devices.

Selective and quasi-continuous switching of ferroelectric Chern insulator devices for neuromorphic computing.

Quantum materials exhibit dissipationless topological edge state transport with quantized Hall conductance, offering notable potential for fault-tolerant computing technologies. However, the development of topological edge state-based computing devices remains a challenge. Here we report the selective and quasi-continuous ferroelectric switching of topological Chern insulator devices, showcasing a proof-of-concept demonstration in noise-immune neuromorphic computing. We fabricate this ferroelectric Chern insulator device by encapsulating magic-angle twisted bilayer graphene with doubly aligned h-BN layers and observe the coexistence of the interfacial ferroelectricity and the topological Chern insulating states. The observed ferroelectricity exhibits an anisotropic dependence on the in-plane magnetic field. By tuning the amplitude of the gate voltage pulses, we achieve ferroelectric switching between any pair of Chern insulating states in the presence of a finite magnetic field, resulting in 1,280 ferroelectric states with distinguishable Hall resistance levels on a single device. Furthermore, we demonstrate deterministic switching between two arbitrary levels among the record-high number of ferroelectric states. This unique switching capability enables the implementation of a convolutional neural network resistant to external noise, utilizing the quantized Hall conductance levels of the Chern insulator device as weights. Our study provides a promising avenue towards the development of topological quantum neuromorphic computing, where functionality and performance can be drastically enhanced by topological quantum materials.

A new evaluation system for drug-microbiota interactions.

The drug response phenotype is determined by a combination of genetic and environmental factors. The high clinical conversion failure rate of gene-targeted drugs might be attributed to the lack of emphasis on environmental factors and the inherent individual variability in drug response (IVDR). Current evidence suggests that environmental variables, rather than the disease itself, are the primary determinants of both gut microbiota composition and drug metabolism. Additionally, individual differences in gut microbiota create a unique metabolic environment that influences the in vivo processes underlying drug absorption, distribution, metabolism, and excretion (ADME). Here, we discuss how gut microbiota, shaped by both genetic and environmental factors, affects the host's ADME microenvironment within a new evaluation system for drug-microbiota interactions. Furthermore, we propose a new top-down research approach to investigate the intricate nature of drug-microbiota interactions in vivo. This approach utilizes germ-free animal models, providing foundation for the development of a new evaluation system for drug-microbiota interactions.

NMR Studies of the Interactions between Sialyllactoses and the Polysialytransferase Domain for Polysialylation Inhibition.

It is known that sialyllactose (SL) in mammalians is a major source of sialic acid (Sia), which can further form cytidine monophosphate sialic acid (CMP-Sia), and the final product is polysialic acid (polySia) using polysialyltransferases (polySTs) on the neural cell adhesion molecule (NCAM). This process is called NCAM polysialylation. The overexpression of polysialylation is strongly related to cancer cell migration, invasion, and metastasis. In order to inhibit the overexpression of polysialylation, in this study, SL was selected as an inhibitor to test whether polysialylation could be inhibited. Our results suggest that the interactions between the polysialyltransferase domain (PSTD) in polyST and CMP-Siaand the PSTD and polySia could be inhibited when the 3'-sialyllactose (3'-SL) or 6'-sialyllactose (6'-SL) concentration is about 0.5 mM or 6'-SL and 3 mM, respectively. The results also show that SLs (particularly for 3'-SL) are the ideal inhibitors compared with another two inhibitors, low-molecular-weight heparin (LMWH) and cytidine monophosphate (CMP), because 3'-SL can not only be used to inhibit NCAM polysialylation, but is also one of the best supplements for infant formula and the gut health system.

Electrical switching of Ising-superconducting nonreciprocity for quantum neuronal transistor.

Nonreciprocal quantum transport effect is mainly governed by the symmetry breaking of the material systems and is gaining extensive attention in condensed matter physics. Realizing electrical switching of the polarity of the nonreciprocal transport without external magnetic field is essential to the development of nonreciprocal quantum devices. However, electrical switching of superconducting nonreciprocity remains yet to be achieved. Here, we report the observation of field-free electrical switching of nonreciprocal Ising superconductivity in Fe3GeTe2/NbSe2 van der Waals (vdW) heterostructure. By taking advantage of this electrically switchable superconducting nonreciprocity, we demonstrate a proof-of-concept nonreciprocal quantum neuronal transistor, which allows for implementing the XOR logic gate and faithfully emulating biological functionality of a cortical neuron in the brain. Our work provides a promising pathway to realize field-free and electrically switchable nonreciprocity of quantum transport and demonstrate its potential in exploring neuromorphic quantum devices with both functionality and performance beyond the traditional devices.

Prevalence and trends of Chlamydia trachomatis infection in female sex workers and men who have sex with men in China: a systematic review and meta-analysis.

INTRODUCTION: Chlamydia trachomatis infection can cause a significant disease burden in high-risk populations. This study aimed to assess the overall prevalence of C. trachomatis infection, and determine the long-term trends and geographic distribution of this infection among female sex workers (FSWs) and men who have sex with men (MSM) in China. METHODS: The PubMed, Web of Science, CNKI, Wanfang Data and VIP databases were searched from 1 January 1990 through 30 April 2023. Publications in which C. trachomatis infection was detected using nucleic acid amplification tests (NAATs) were included. The Q test and I2 statistics were used to assess the heterogeneity between studies. A random-effect model was used to estimate the pooled prevalence of C. trachomatis infection. Subgroup, meta-regression, and sensitivity analyses were performed to explore the sources of heterogeneity. Publication bias was evaluated using Egger's test. Trend analysis of the prevalence was performed using the Jonckheere-Terpstra trend test method. RESULTS: Sixty-one studies were eligible for inclusion (including 38 for FSWs and 23 for MSM). The pooled prevalence of C. trachomatis infection was 19.5% (95% CI: 16.4, 23.0) among FSWs and 12.7% (95% CI: 9.2, 17.7) in the rectum, 6.4% (95% CI: 5.3, 7.8) in the urethra and 1.3% (95% CI: 0.8, 2.1) in the oropharynx from MSM in China. The subgroup analyses showed that the sample size, study period, study region, specimen collection type, molecular diagnosis method, and recruitment site could explain some heterogeneity among studies of FSWs, and the publication language, study period, study region, molecular diagnosis method, and specimen collection anatomical site could explain some heterogeneity among studies of MSM. From 1998 to 2004, 2005 to 2009, 2010 to 2015, and 2016 to 2021, the pooled prevalence of C. trachomatis infection among FSWs were 30.3%, 19.9%, 21.4%, and 11.3%, respectively. For MSM, the pooled prevalence from 2003 to 2009, 2010 to 2015, and 2016 to 2022 were 7.8%, 4.7%, and 6.5%, respectively. However, no overall decline in the prevalence of C. trachomatis infection was observed among FSWs (z = -1.51, P = 0.13) or MSM (z = -0.71, P = 0.48) in China. CONCLUSIONS: The prevalence of C. trachomatis infection was high in these two high-risk populations in China. The findings of this study provide evidence for the formulation of effective surveillance and screening strategies for the prevention and control of C. trachomatis infection among these two specific populations.

Molecular analyses display the increasing diversity of Podostemaceae in China.

•Four newly recorded species of Podostemaceae from southern China were identified by molecular and morphological evidence.•17 plastomes of Podostemaceae were newly sequenced and two novel polymorphic barcodes (ccsA and ndhA) detected.•Our findings reveal greater species richness (15 species from five genera) of Podostemaceae in China and supply molecular resources for research on taxonomy and phylogenomics of this enigmatic aquatic family.

The Bifunctional Effects of Lactoferrin (LFcinB11) in Inhibiting Neural Cell Adhesive Molecule (NCAM) Polysialylation and the Release of Neutrophil Extracellular Traps (NETs).

The expression of polysialic acid (polySia) on the neuronal cell adhesion molecule (NCAM) is called NCAM-polysialylation, which is strongly related to the migration and invasion of tumor cells and aggressive clinical status. Thus, it is important to select a proper drug to block tumor cell migration during clinical treatment. In this study, we proposed that lactoferrin (LFcinB11) may be a better candidate for inhibiting NCAM polysialylation when compared with CMP and low-molecular-weight heparin (LMWH), which were determined based on our NMR studies. Furthermore, neutrophil extracellular traps (NETs) represent the most dramatic stage in the cell death process, and the release of NETs is related to the pathogenesis of autoimmune and inflammatory disorders, with proposed involvement in glomerulonephritis, chronic lung disease, sepsis, and vascular disorders. In this study, the molecular mechanisms involved in the inhibition of NET release using LFcinB11 as an inhibitor were also determined. Based on these results, LFcinB11 is proposed as being a bifunctional inhibitor for inhibiting both NCAM polysialylation and the release of NETs.

Mouse serum albumin induces neuronal apoptosis and tauopathies.

The elderly frequently present impaired blood-brain barrier which is closely associated with various neurodegenerative diseases. However, how the albumin, the most abundant protein in the plasma, leaking through the disrupted BBB, contributes to the neuropathology remains poorly understood. We here demonstrated that mouse serum albumin-activated microglia induced astrocytes to A1 phenotype to remarkably increase levels of Elovl1, an astrocytic synthase for very long-chain saturated fatty acids, significantly promoting VLSFAs secretion and causing neuronal lippoapoptosis through endoplasmic reticulum stress response pathway. Moreover, MSA-activated microglia triggered remarkable tau phosphorylation at multiple sites through NLRP3 inflammasome pathway. Intracerebroventricular injection of MSA into the brains of C57BL/6J mice to a similar concentration as in patient brains induced neuronal apoptosis, neuroinflammation, increased tau phosphorylation, and decreased the spatial learning and memory abilities, while Elovl1 knockdown significantly prevented the deleterious effect of MSA. Overall, our study here revealed that MSA induced tau phosphorylation and neuron apoptosis based on MSA-activated microglia and astrocytes, respectively, showing the critical roles of MSA in initiating the occurrence of tauopathies and cognitive decline, and providing potential therapeutic targets for MSA-induced neuropathology in multiple neurodegenerative disorders.

Correlations between ecosystem service value and landscape ecological risk and its spatial heterogeneity in Jilin Province, China.

Exploring the correlations between ecosystem service value (ESV) and landscape ecological risk and the driving factors of their spatial variations is crucial for maintaining regional ecological security and promoting sustainable human well-being. We carried out a grid resampling size of 5 km×5 km assessment units of Jilin Pro-vince based on the remote sensing monitoring data of land use in 2000, 2005, 2010, 2015, and 2020. We quantitatively evaluated the landscape ecological risk and ESV, and analyzed their spatial-temporal variations. Employing bivariate spatial autocorrelation analysis and the geographical detector models, we examined the correlation between the landscape ecological risk and ESV and explored the driving factors for their spatial variations. The results showed that ESV in Jilin Province decreased from 385.895 billion yuan to 378.211 billion yuan during 2000-2020. The eastern region was dominated by extremely low risk, medium risk, and low risk areas. In contrast, the western region was mainly composed of extremely high risk and high risk areas. There was a significant negative correlation and spatial negative correlation between landscape ecological risk and ESV in Jilin Province. Human activity and land use type were the important driving factors for spatial differentiation in both landscape ecological risk and ESV. Our findings suggested that scientific land use regulation and appropriate control of human activities are critically needed to optimize Jilin Province's ecological environment.

Thrombomodulin reduces α-synuclein generation and ameliorates neuropathology in a mouse model of Parkinson's disease.

The neurotoxic α-synuclein (α-syn) oligomers play an important role in the occurrence and development of Parkinson's disease (PD), but the factors affecting α-syn generation and neurotoxicity remain unclear. We here first found that thrombomodulin (TM) significantly decreased in the plasma of PD patients and brains of A53T α-syn mice, and the increased TM in primary neurons reduced α-syn generation by inhibiting transcription factor p-c-jun production through Erk1/2 signaling pathway. Moreover, TM decreased α-syn neurotoxicity by reducing the levels of oxidative stress and inhibiting PAR1-p53-Bax signaling pathway. In contrast, TM downregulation increased the expression and neurotoxicity of α-syn in primary neurons. When TM plasmids were specifically delivered to neurons in the brains of A53T α-syn mice by adeno-associated virus (AAV), TM significantly reduced α-syn expression and deposition, and ameliorated the neuronal apoptosis, oxidative stress, gliosis and motor deficits in the mouse models, whereas TM knockdown exacerbated these neuropathology and motor dysfunction. Our present findings demonstrate that TM plays a neuroprotective role in PD pathology and symptoms, and it could be a novel therapeutic target in efforts to combat PD. Schematic representation of signaling pathways of TM involved in the expression and neurotoxicity of α-syn. A TM decreased RAGE, and resulting in the lowered production of p-Erk1/2 and p-c-Jun, and finally reduce α-syn generation. α-syn oligomers which formed from monomers increase the expression of p-p38, p53, C-caspase9, C-caspase3 and Bax, decrease the level of Bcl-2, cause mitochondrial damage and lead to oxidative stress, thus inducing neuronal apoptosis. TM can reduce intracellular oxidative stress and inhibit p53-Bax signaling by activating APC and PAR-1. B The binding of α-syn oligomers to TLR4 may induce the expression of IL-1ß, which is subsequently secreted into the extracellular space. This secreted IL-1ß then binds to its receptor, prompting p65 to translocate from the cytoplasm into the nucleus. This translocation downregulates the expression of KLF2, ultimately leading to the suppression of TM expression. By Figdraw.

Acupuncture and related acupoint therapies for smoking cessation: An umbrella review and updated meta-analysis.

INTRODUCTION: Acupuncture and related acupoint therapies have been widely used for smoking cessation. Some relevant systematic reviews (SRs) have been published. There is a need to summarize and update the evidence to inform practice and decision-making. METHODS: Eight databases were searched from their inception to December 2023. SRs, any randomized controlled trials (RCTs) comparing acupuncture therapies with sham acupuncture, pharmacotherapy, behavioral therapy, or no treatment, were included. The primary outcome was the abstinence rate. AMSTAR-2 was employed to assess the quality of SRs. An updated meta-analysis was conducted based on SRs and RCTs. Data were synthesized using risk ratios (RR) with 95% confidence intervals (CIs). The GRADE approach was employed to assess the certainty of the updated evidence. RESULTS: Thirteen SRs and 20 RCTs outside of the SRs were identified. The SRs were of low or very low quality by AMSTAR-2. Sixteen (80%) RCTs were at high risk of performance bias. Eight acupuncture and related acupoint therapies were involved. The short-term (≤6 months) abstinence rate outcome was summarized as follows. Most SRs suggested that filiform needle acupuncture or acupressure had a better effect than sham acupuncture, but the findings were inconsistent. The updated meta-analysis also suggested that filiform needle acupuncture was more effective than sham acupuncture (RR=1.44; 95% CI: 1.02-2.02; I2 = 66%; low certainty; 9 RCTs, n=1358). Filiform needle acupuncture combined with acupressure was comparable to nicotine patches (RR=0.99; 95% CI: 0.74-1.32; low certainty; 6 RCTs, n= 524). Acupressure was superior to counseling (RR=1.46; 95% CI: 1.14-1.87; I2=5%; low certainty; 8 RCTs, n=595). No serious adverse events were reported in these SRs or RCTs. CONCLUSIONS: Low certainty evidence suggests that filiform needle acupuncture and auricular acupressure appear to be safe and effective in achieving short-term smoking cessation. However, long-term follow-up data are needed.

On-device phase engineering.

In situ tailoring of two-dimensional materials' phases under external stimulus facilitates the manipulation of their properties for electronic, quantum and energy applications. However, current methods are mainly limited to the transitions among phases with unchanged chemical stoichiometry. Here we propose on-device phase engineering that allows us to realize various lattice phases with distinct chemical stoichiometries. Using palladium and selenide as a model system, we show that a PdSe2 channel with prepatterned Pd electrodes can be transformed into Pd17Se15 and Pd4Se by thermally tailoring the chemical composition ratio of the channel. Different phase configurations can be obtained by precisely controlling the thickness and spacing of the electrodes. The device can be thus engineered to implement versatile functions in situ, such as exhibiting superconducting behaviour and achieving ultralow-contact resistance, as well as customizing the synthesis of electrocatalysts. The proposed on-device phase engineering approach exhibits a universal mechanism and can be expanded to 29 element combinations between a metal and chalcogen. Our work highlights on-device phase engineering as a promising research approach through which to exploit fundamental properties as well as their applications.

Quercitrin improves cardiac remodeling following myocardial infarction by regulating macrophage polarization and metabolic reprogramming.

The death and disability caused by myocardial infarction is a health problem that needs to be addressed worldwide, and poor cardiac repair and fibrosis after myocardial infarction seriously affect patient recovery. Postmyocardial infarction repair by M2 macrophages is of great significance for ventricular remodeling. Quercitrin (Que) is a common flavonoid in fruits and vegetables that has antioxidant, anti-inflammatory, antitumor and other effects, but whether it has a role in the treatment of myocardial infarction is unclear. In this study, we constructed a mouse myocardial infarction model and administered Que. We found through cardiac ultrasound that Que administration improved cardiac ejection fraction and reduced ventricular remodeling. Staining of heart sections and detection of fibrosis marker protein levels revealed that Que administration slowed fibrosis after myocardial infarction. Flow cytometry showed that the proportion of M2 macrophages in the mouse heart was increased and that the expression levels of M2 macrophage markers were increased in the Que-treated group. Finally, we identified by metabolomics that Que reduces glycolysis, increases aerobic phosphorylation, and alters arginine metabolic pathways, polarizing macrophages toward the M2 phenotype. Our research lays the foundation for the future application of Que in myocardial infarction and other cardiovascular diseases.

Endoplasmic Reticulum-Targeting Self-Assembly Nanosheets Promote Autophagy and Regulate Immunosuppressive Tumor Microenvironment for Efficient Photodynamic Immunotherapy.

The poor efficiency and low immunogenicity of photodynamic therapy (PDT), and the immunosuppressive tumor microenvironment (ITM) lead to tumor recurrence and metastasis. In this work, TCPP-TER-Zn@RSV nanosheets (TZR NSs) that co-assembled from the endoplasmic reticulum (ER)-targeting photosensitizer TCPP-TER-Zn nanosheets (TZ NSs for short) and the autophagy promoting and indoleamine-(2, 3)-dioxygenase (IDO) inhibitor-like resveratrol (RSV) are fabricated to enhance antitumor PDT. TZR NSs exhibit improved therapeutic efficiency and amplified immunogenic cancer cell death (ICD) by ER targeting PDT and ER autophagy promotion. TZR NSs reversed the ITM with an increase of CD8+ T cells and reduce of immunosuppressive Foxp3 regulatory T cells, which effectively burst antitumor immunity thus clearing residual tumor cells. The ER-targeting TZR NSs developed in this paper presents a simple but valuable reference for high-efficiency tumor photodynamic immunotherapy.

Interfacial magnetic spin Hall effect in van der Waals Fe3GeTe2/MoTe2 heterostructure.

The spin Hall effect (SHE) allows efficient generation of spin polarization or spin current through charge current and plays a crucial role in the development of spintronics. While SHE typically occurs in non-magnetic materials and is time-reversal even, exploring time-reversal-odd (T-odd) SHE, which couples SHE to magnetization in ferromagnetic materials, offers a new charge-spin conversion mechanism with new functionalities. Here, we report the observation of giant T-odd SHE in Fe3GeTe2/MoTe2 van der Waals heterostructure, representing a previously unidentified interfacial magnetic spin Hall effect (interfacial-MSHE). Through rigorous symmetry analysis and theoretical calculations, we attribute the interfacial-MSHE to a symmetry-breaking induced spin current dipole at the vdW interface. Furthermore, we show that this linear effect can be used for implementing multiply-accumulate operations and binary convolutional neural networks with cascaded multi-terminal devices. Our findings uncover an interfacial T-odd charge-spin conversion mechanism with promising potential for energy-efficient in-memory computing.

Selection of reference genes in liproxstatin-1-treated K562 Leukemia cells via RT-qPCR and RNA sequencing.

BACKGROUND: Reverse transcription quantitative polymerase chain reaction (RT-qPCR) can accurately detect relative gene expression levels in biological samples. However, widely used reference genes exhibit unstable expression under certain conditions. METHODS AND RESULTS: Here, we compared the expression stability of eight reference genes (RPLP0, RPS18, RPL13, EEF1A1, ß-actin, GAPDH, HPRT1, and TUBB) commonly used in liproxstatin-1 (Lip-1)-treated K562 cells using RNA-sequencing and RT-qPCR. The expression of EEF1A1, ACTB, GAPDH, HPRT1, and TUBB was considerably lower in cells treated with 20 µM Lip-1 than in the control, and GAPDH also showed significant downregulation in the 10 µM Lip-1 group. Meanwhile, when we used geNorm, NormFinder, and BestKeeper to compare expression stability, we found that GAPDH and HPRT1 were the most unstable reference genes among all those tested. Stability analysis yielded very similar results when geNorm or BestKeeper was used but not when NormFinder was used. Specifically, geNorm and BestKeeper identified RPL13 and RPLP0 as the most stable genes under 20 µM Lip-1 treatment, whereas RPL13, EEF1A1, and TUBB were the most stable under 10 µM Lip-1 treatment. TUBB and EEF1A1 were the most stable genes in both treatment groups according to the results obtained using NormFinder. An assumed most stable gene was incorporated into each software to validate the accuracy. The results suggest that NormFinder is not an appropriate algorithm for this study. CONCLUSIONS: Stable reference genes were recognized using geNorm and BestKeeper but not NormFinder. Overall, RPL13 and RPLP0 were the most stable reference genes under 20 µM Lip-1 treatment, whereas RPL13, EEF1A1, and TUBB were the most stable genes under 10 µM Lip-1 treatment.

Nanodrugs mediate TAMs-related arginine metabolism interference to boost photodynamic immunotherapy.

As a potential treatment strategy for low immunogenic triple negative breast cancer (TNBC), photodynamic therapy (PDT) induced antitumor immunotherapy is greatly limited by the immunosuppressive tumor microenvironment (ITM), especially the M2 phenotype tumor-associated macrophages (TAMs). The balance of arginine metabolism plays an important role in TAMs polarization. Herein, a multifunctional nanoplatform (defined as HN-HFPA) was employed to burst the anti-tumor immunity of TNBC post PDT by reeducating TAMs through interfering the TAMs-associated arginine metabolism. The L-arginine (L-Arg) was loaded in the hollow cavity of HN-HFPA, which could not only generate nitric oxide (NO) for tumor therapy, but also serve as a substrate of arginine metabolism pathway. As an inhibitor of arginases-1 (Arg-1) of M2 TAMs, L-norvaline (L-Nor) was modified to the hyaluronic acid (HA), and coated in the surface of HFPA. After degradation of HA by hyaluronidase in tumor tissue and GSH-mediated disintegration, HN-HFPA depleted intracellular GSH, produced remarkable reactive oxygen species (ROS) under light irradiation and released L-Arg to generate NO, which induced tumor immunogenic cell death (ICD). Real-time ultrasound imaging of tumor was realized taking advantage of the gas feature of NO. The L-Nor suppressed the Arg-1 overexpressed in M2, which skewed the balance of arginine metabolism and reversed the ITM with increased ratios of M1 and CD8+ T cells, finally resulted in amplified antitumor immune response and apparent tumor metastasis inhibition. This study remodeled ITM to strengthen immune response post PDT, which provided a promising treatment strategy for TNBC.