TRAF6 enhances PD-L1 expression through YAP1-TFCP2 signaling in melanoma.

Immunotherapy represented by programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies has led tumor treatment into a new era. However, the low overall response rate and high incidence of drug resistance largely damage the clinical benefits of existing immune checkpoint therapies. Recent studies correlate the response to PD-1/PD-L1 blockade with PD-L1 expression levels in tumor cells. Hence, identifying molecular targets and pathways controlling PD-L1 protein expression and stability in tumor cells is a major priority. In this study, we performed a Stress and Proteostasis CRISPR interference screening to identify PD-L1 positive modulators. Here, we identified TRAF6 as a critical regulator of PD-L1 in melanoma cells. As a non-conventional E3 ubiquitin ligase, TRAF6 is inclined to catalyze the synthesis and linkage of lysine-63 (K63) ubiquitin which is related to the stabilization of substrate proteins. Our results showed that suppression of TRAF6 expression down-regulates PD-L1 expression on the membrane surface of melanoma cells. We then used in vitro and in vivo assays to investigate the biological function and mechanism of TRAF6 and its downstream YAP1/TFCP2 signaling in melanoma. TRAF6 stabilizes YAP1 by K63 poly-ubiquitination modification, subsequently promoting the formation of YAP1/TFCP2 transcriptional complex and PD-L1 transcription. Inhibition of TRAF6 by Bortezomib enhanced cytolytic activity of CD8+ T cells by reduction of endogenous PD-L1. Notably, Bortezomib enhances anti-tumor immunity to an extent comparable to anti-PD-1 therapies with no obvious toxicity. Our findings reveal the potential of inhibiting TRAF6 to stimulate internal anti-tumor immunological effect for TRAF6-PD-L1 overexpressing cancers.

Exposure levels and determinants of placental polybrominated diphenyl ethers in Chinese pregnant women.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are a group of widely used chemicals and humans are exposed to them in their daily life. PBDEs exposure during pregnancy may have adverse effects on pregnant women and their fetuses. Nevertheless, limited information is available on the levels and determinants of PBDEs exposure in Chinese pregnant women. METHODS: The internal exposure levels of eight PBDEs (BDE-28, 47, 99, 100, 153, 154, 183, and 209) in placental samples of 1280 pregnant women from Zunyi birth cohort were analyzed using gas chromatography tandem mass spectrometry. All PBDEs concentrations were lipid adjusted (ng/g lw). Determinants of exposure were assessed by multivariable logistic regression model. RESULTS: Eight PBDE homologues were quantifiable in more than 70% of the samples. The highest median concentrations were found for BDE-209 (2.78 ng/g lw), followed by BDE-153 (1.00 ng/g lw) and BDE-183 (0.93 ng/g lw). The level of ΣPBDEs ranged from 0.90 to 308.78 ng/g lw, with a median concentration of 10.02 ng/g lw. Multivariate logistic regression analysis showed that maternal age older than 30 years old (OR: 1.59; 95% CI: 1.14, 2.23), pre-pregnancy obesity (1.51; 1.08, 2.10), home renovation within 2 years (1.43; 1.08, 1.91), spending more time outdoors during pregnancy (0.70; 0.55, 0.89), high consumption of fish/seafood (1.46; 1.13, 1.90) and eggs (1.44; 1.04, 2.00), male infant sex (1.69; 1.18, 2.42) were associated with PBDEs exposure. CONCLUSION: The study population is generally exposed to PBDEs, of which BDE-209 is the dominant congener, indicating extensive application of products containing deca-BDE mixtures. Maternal age, pre-pregnancy BMI, home decoration, average outdoor time during pregnancy, fish, seafood, eggs consumption, and fetal sex were exposure-determinning factors. This study contributes to the knowledge on region-specific PBDEs contamination in pregnant women and related risk factors.

Recent Advances in Flexible Multifunctional Sensors.

Wearable electronics have received extensive attention in human-machine interactions, robotics, and health monitoring. The use of multifunctional sensors that are capable of measuring a variety of mechanical or environmental stimuli can provide new functionalities for wearable electronics. Advancements in material science and system integration technologies have contributed to the development of high-performance flexible multifunctional sensors. This review presents the main approaches, based on functional materials and device structures, to improve sensing parameters, including linearity, detection range, and sensitivity to various stimuli. The details of electrical, biocompatible, and mechanical properties of self-powered sensors and wearable wireless systems are systematically elaborated. Finally, the current challenges and future developmental directions are discussed to offer a guide to fabricate advanced multifunctional sensors.

Metabolomics reveals the impact of nitrogen combined with the zinc supply on zinc availability in calcareous soil via root exudates of winter wheat (Triticum aestivum).

A possible mechanism for the improved availability of zinc (Zn) in soil by combining nitrogen (N) with Zn supply was investigated based on the root exudates of winter wheat. N, Zn supply as well as their combination significantly regulated nine root exudates in winter wheat; in which, the secretion of cis-aconitic acid involving in the TCA cycle, C5-branched dibasic acid metabolism, glyoxylate and dicarboxylate metabolism and 2-oxocarboxylic acid metabolism was upregulated by N, Zn supply as well as their combination. N-Zn combination induced the activities of citrate synthase and cis-aconitase in roots and shoots of winter wheat thus to increase the concentrations of citric and aconitic acid; the decrease of isocitric acid concentrations in shoots indicated the inhibited conversion of aconitic acid to isocitric acid by N-Zn combination. It revealed a possible reason for the enhanced secretion of cis-aconitic acid by N-Zn combination. Exogenous addition of 10 µ plant-1 cis-aconitate significantly increased available Zn concentrations in soil and Zn concentrations in winter wheat under N-Zn combination. Thus, the N-Zn combination regulated the metabolism of cis-aconitic acid in winter wheat, thus enhancing the secretion of cis-aconitic acid to increase the bioavailability of Zn in soil.

TNF-R1 Cellular Nanovesicles Loaded on the Thermosensitive F-127 Hydrogel Enhance the Repair of Scalded Skin.

Excessive inflammatory response after severe scalding is an important cause of delayed wound healing and is even life-threatening. Tumor necrosis factor α (TNF-α) is a key pro-inflammatory factor of skin trauma. Interacting with tumor necrosis factor receptor 1 (TNF-R1), TNF-α causes excessive inflammation and poor prognosis by activating NF-κB pathway. Antagonizing high levels of TNF-α is one of the therapeutic approaches for diseases associated with the overactivation of inflammatory responses. However, the available monoclonal antibodies are limited in their application due to their complex preparation process, high price, and the lack of cell targeting ability leading to systemic toxicity and side effects. In this study, by using a genetic bioengineering technique, we modified TNF-R1 on the cell membrane surface-derived nanovesicles (NVs). We confirmed that TNF-R1 NVs stably expressed TNF-R1 on the membrane surface and interacted with its ligand TNF-α. Furthermore, TNF-R1 NVs competitively antagonized the effect of TNF-α in the wound healing assay in vitro. In the scalded mouse model, TNF-R1 NVs were released continuously from the thermosensitive hydrogel Pluronic F-127, resulting in less inflammation and better wound healing. Our results revealed TNF-R1 NVs as promising cell-free therapeutic agents in alleviating TNF-α-mediated pro-inflammatory signaling and promoting wound repair.

Risk assessment and environmental determinants of urinary phthalate metabolites in pregnant women in Southwest China.

Pregnant women are widely exposed to phthalic acid esters (PAEs) that are commonly used in most aspects of modern life. However, few studies have examined the cumulative exposure of pregnant women to a variety of PAEs derived from the living environmental conditions in China. Therefore, this study aimed to determine the urinary concentrations of nine PAE metabolites in pregnant women, examine the relationship between urinary concentrations and residential characteristics, and conduct a risk assessment analysis. We included 1,888 women who were in their third trimester of pregnancy, and we determined their urinary concentrations of nine PAE metabolites using high-performance gas chromatography-mass spectrometry. The risk assessment of exposure to PAEs was calculated based on the estimated daily intake. A linear regression model was used to analyze the relationship between creatinine-adjusted PAE metabolite concentrations and residential characteristics. The detection rate of five PAE metabolites in the study population was > 90%. Among the PAE metabolites adjusted by creatinine, the urinary metabolite concentration of monobutyl phthalate was found to be the highest. Residential factors, such as housing type, proximity to streets, recent decorations, lack of ventilation in the kitchen, less than equal to three rooms, and the use of coal/kerosene/wood/wheat straw fuels, were all significantly associated with high PAE metabolite concentrations. Due to PAE exposure, ~ 42% (n = 793) of the participants faced potential health risks, particularly attributed to dibutyl phthalate, diisobutyl phthalate, and di(2-ethyl)hexyl phthalate exposure. Living in buildings and using coal/kerosene/wood/wheat straw as domestic fuel can further increase the risks.

Effects of exposure to phthalate during early pregnancy on gestational diabetes mellitus: a nested case-control study with propensity score matching.

Owing to the complexity of phthalates (PAEs) components and the diversity of their sources, the health hazards of their metabolites to pregnant women remain unclear. This study aimed to explore the relationship between exposure to PAEs during early pregnancy and gestational diabetes mellitus (GDM) in rural pregnant women. We assessed pregnant women with (n = 338) or without (n = 3082) GDM from the ongoing Zunyi Birth Cohort. Participants' urine samples were collected to measure the levels of 10 metabolites of PAEs. GDM was diagnosed using the 75-g oral glucose tolerance test at 24-28 weeks of gestation. We adopted propensity score matching based on GDM-related factors and pregnant women's backgrounds to establish two groups of 338 patients: those with or without GDM. In the cohort, we included 5734 pregnant women; 519 of them developed GDM, yielding a GDM incidence rate of 9.05%. Urinary concentrations of monooctyl phthalate (MOP), mono-benzyl phthalate (MBzP), mono(2-ethyl-5-oxyhexyl) phthalate (MEOHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) during early pregnancy were significantly associated with GDM (P < 0.05). Logistic regression models revealed that MEOHP in the urine was positively associated with GDM (odds ratio [OR] = 1.55; 95% confidence interval [CI]: 1.00-2.39). Furthermore, restricted cubic spline models revealed that urine MEOHP concentrations greater than 15.6 µg/L were positively associated with GDM, and approximately 23.5% pregnant women had urine MEOHP concentrations greater than 15.6 µg/L. Thus, approximately 23.5% of pregnant women were at the risk of developing GDM due to MEOHP, which suggested that pregnant women should reduce the use of packaged food and cosmetics to reduce the risk of GDM. However, further molecular biology experiments are required to confirm these findings and to elucidate the underlying mechanisms.

Characteristics of exposure to 10 polycyclic aromatic hydrocarbon metabolites among pregnant women: cohort of pregnant women in Zunyi, southwest China.

OBJECTIVE: Our aim was to elucidate the polycyclic aromatic hydrocarbon (PAH) metabolites exposure levels of pregnant women in the underdeveloped region of Zunyi, southwest China. METHODS: Sociodemographic information was collected via questionnaires, and urine samples were collected at the same time. A total of 3047 pregnant women participated in the study. Gas chromatography/mass spectrometry was used to detect the urine concentrations of 10 PAH metabolites. A generalised linear model (GLM) was used to identify predictive factors of PAH metabolites. RESULTS: All PAH metabolites had a detection rate greater than 60% (67.21%-90.57%) except for 4-OH-PHE at 55.54%. The median concentrations were 0.02-0.11 µg/g Cre except for 1-OH-NAP, 2-OH-NAP, 2-OH-FLU and 9-OH-FLU (0.36-0.50 µg/g Cre). The cluster analysis identified the phenanthrene and fluorene metabolite clusters (containing no other metabolites), while naphthalene metabolites (1-OH-NAP, 2-OH-NAP) could not be clustered without other metabolites. GLM analysis identified that pregnant women with the following characteristics have high urinary concentration of PAH metabolites: overweight, in the last trimester of pregnancy, distance between their house and main traffic lines as <5 m, use fuel for cooking, passive smoking, renovated their residence for less than 3 years, middle family income and office workers. CONCLUSION: The results clarified pregnant women from the economically underdeveloped area could be the victims of PAHs. In addition, PAHs present a demographic and seasonal differential distribution, which will aid in the development of targeted interventions and reduce exposure to PAHs during pregnancy.

Maternal urine phthalate metabolite exposure and miscarriage risk: a nested case-control study of the Zunyi Birth Cohort.

Phthalates (PAEs) are widespread persistent organic pollutants and endocrine disruptors. However, the associations between PAE exposure and the risk of miscarriage in humans are unclear, and an insufficient number of studies have evaluated the possible threshold or dose-dependent effects of first trimester PAE exposure on miscarriage risk. Our research measured the levels of mono-methyl phthalate (MMP), mono-ethyl phthalate, mono-isobutyl phthalate, MiBP mono-butyl phthalate (MBP), mono-octyl phthalate, mono-benzyl phthalate, mono(2-ethylhexyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate, and mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) in maternal urine collected in early gestation between 150 pregnancies ending in miscarriage and 150 pregnancies with live birth. We also estimated the odds ratios (ORs) and 95% confidence intervals (CIs) for miscarriage and each PAE as a continuous variable or quartile. A restrictive cubic splines was used to assess dose-dependent effects after controlling for maternal characteristics (e.g., age, educational level). we identified monotonically increasing dose-dependent effects of MEHHP and MMP on the risk of miscarriage. The largest effect estimates were approximately threefold higher for the highest MBP (OR = 2.57; 95% CI = 1.32-5.01) or MMP quartile (OR = 3.57; 95% CI = 1.82-7.00) and two-fold higher for the highest MEHHP quartile (OR = 2.12; 95% CI = 1.10-4.11). Our research preliminarily obtained possible thresholds of MBP, MEHHP, and MMP which were 18.07, 2.38, and 0.80 µg/g Cr for the risk of miscarriage, respectively. First-trimester exposure to MBP, MEHHP, and MMP exceeding certain thresholds increases the risk of miscarriage.

PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia.

Mutations in the plant homeodomain-like finger protein 6 (PHF6) gene are strongly associated with acute myeloid (AML) and T-cell acute lymphoblastic leukemia (T-ALL). In this study, we demonstrated that PHF6 can bind to H3K9me3 and H3K27me1 on the nucleolar chromatin and recruit histone methyltransferase SUV39H1 to the rDNA locus. The deletion of PHF6 caused a decrease in the recruitment of SUV39H1 to rDNA gene loci, resulting in a reduction in the level of H3K9me3 and the promotion of rDNA transcription. The knockdown of either SUV39H1 or PHF6 significantly attenuated the effects of increase in H3K9me3 and suppressed the transcription of rDNA induced by the overexpression of the other interacting partner, thereby establishing an interdependent relationship between PHF6 and SUV39H1 in their control of rRNA transcription. The PHF6 clinical mutants significantly impaired the ability to bind and recruit SUV39H1 to the rDNA loci, resulting in an increase in rDNA transcription activity, the proliferation of in vitro leukemia cells, and the growth of in vivo mouse xenografts. Importantly, significantly elevated levels of pre-rRNA were observed in clinical AML patients who possessed a mutated version of PHF6. The specific rDNA transcription inhibitor CX5461 significantly reduced the resistance of U937 AML cells deficient in PHF6 to cytarabine, the drug that is most commonly used to treat AML. Collectively, we revealed a novel molecular mechanism by which PHF6 recruits methyltransferase SUV39H1 to the nucleolar region in leukemia and provided a potential therapeutic target for PHF6-mutant leukemia.

Association between exposures to phthalate metabolites and preterm birth and spontaneous preterm birth: A systematic review and meta-analysis.

Emerging evidence from observational studies proves the association between preterm birth (PTB) and phthalate metabolites; however, such findings are inconsistent and inconclusive. This meta-analysis aimed to clarify this association by accessing the connection between 11 phthalate metabolites and PTB, and 6 phthalate metabolites and spontaneous PTB. The PubMed, Embase, and WOS (Web of Science) databases were searched up to July 2020. Seven prospective studies met the inclusion criteria. Pooled odds ratios (OR) with 95 % confidence intervals (CIs) were calculated for risk estimation. Our results indicated that mono-n-butyl phthalate (MBP), sum of di-2-ethylhexyl phthalate (ΣDEHP), and mono 3-carboxypropyl phthalate (MCPP) significantly correlated with the risk of PTB (MBP: OR = 1.23, 95 % CI = 1.05-1.45; ΣDEHP: OR = 1.21, 95 % CI =1.01-1.44; MCPP: OR = 1.09, 95 % CI = 1.00-1.19). Pooled results showed that spontaneous PTB was associated with higher urinary levels of mono-ethyl phthalate (MEP), MCPP, mono-isobutyl phthalate (MIBP), and MBP (MBP: OR = 1.27, 95 % CI = 1.02-1.58; MEP: OR = 1.19, 95 % CI = 1.01-1.40; MCPP: OR = 1.15, 95 % CI = 1.02-1.30; MIBP: OR = 1.38, 95 % CI = 1.12-1.71). Overall, we conclude that during pregnancy, MBP, ΣDEHP, and MCPP levels are associated positively with PTB. MBP, MEP, MCPP, and MIBP levels had increased odds of spontaneous PTB. No significant associations were observed between other phthalate metabolites and PTB or spontaneous PTB. Further research is needed to verify these findings and elucidate the association of phthalate levels and PTB.

Vimentin Suppresses Inflammation and Tumorigenesis in the Mouse Intestine.

Vimentin has been implicated in wound healing, inflammation, and cancer, but its functional contribution to intestinal diseases is poorly understood. To study how vimentin is involved during tissue injury and repair of simple epithelium, we induced colonic epithelial cell damage in the vimentin null (Vim-/-) mouse model. Vim-/- mice challenged with dextran sodium sulfate (DSS) had worse colitis manifestations than wild-type (WT) mice. Vim-/- colons also produced more reactive oxygen and nitrogen species, possibly contributing to the pathogenesis of gut inflammation and tumorigenesis than in WT mice. We subsequently describe that CD11b+ macrophages served as the mainly cellular source of reactive oxygen species (ROS) production via vimentin-ROS-pSTAT3-interleukin-6 inflammatory pathways. Further, we demonstrated that Vim-/- mice did not develop colitis-associated cancer model upon DSS treatment spontaneously but increased tumor numbers and size in the distal colon in the azoxymethane/DSS model comparing with WT mice. Thus, vimentin has a crucial role in protection from colitis induction and tumorigenesis of the colon.

Exposure characteristics of phthalate metabolites among the Zunyi cohort of pregnant women in Southwest China.

Reported evidence has increasingly indicated that exposure to phthalates can cause adverse pregnancy outcomes. However, phthalate exposure levels among pregnant women remains unclear. We aimed to evaluate the concentrations and predictors of phthalate metabolites in urine samples of the ongoing Zunyi cohort of pregnant women from Southwest China. The urine samples were collected from 1003 pregnant women during their third trimester of pregnancy. The concentrations of nine phthalate metabolites in urine samples were then determined. Data on socio-demographic profiles of the participants, lifestyle during pregnancy, parity, and sampling season were collected using questionnaires. The detectable rate of phthalate metabolites ranged from 76 to 100%. On average, mono-butyl phthalate exhibited the highest median concentration (62.45 µg/L), while mono-benzyl phthalate exhibited the lowest median concentration (0.04 µg/L). Urine concentrations of phthalate metabolites were significantly higher in older, multiparous, higher body mass index, higher income, and passive smoking during pregnancy participants. The levels of low-molecular-weight phthalate metabolites were highest during the summer. The findings indicate the health of pregnant women and fetuses in Zunyi may be generally harmed by the high exposure of phthalate metabolites, especially by mono-n-butyl phthalate. In addition, phthalate metabolites present a demographic and seasonal differential distribution among the study population. Targeted measures to reduce phthalate exposure for high-risk pregnant women and during high-exposure seasons may have potential benefits for maternal and fetal health protection.

Dependence of Creep Strain and Fatigue Behavior on Surface Characteristics of Resistive Strain Gauges.

Creep behavior and fatigue life are important performance indexes that affect the long-term stability of resistive strain gauges. The resistive strain gauges, fabricated with wet etching and resistance trimming, present micro-morphology such as textures and uneven edges on the surface and side-wall profile of sensitive grids. This paper observed the micro-morphology of the sensitive grids by microscope and analyzed its range of geometric dimensions. A sine function was used to establish equivalent geometric models for the surface textures and side-wall profile. Based on time hardening theory and the S-N curve, the dependence of micro-morphology of metal resistive strain gauges on creep behavior and fatigue life was studied. The results indicate that the roughness of micro-morphology has an influence on creep behavior and fatigue life. The surface textures and side-wall profile lead to the increase of creep strain and the decrease of fatigue life in varying degrees. When 60% of the ultimate stress of the strain gauges is loaded, the average creep strain in steady-state calculated by the maximum roughness of the side-wall profile reaches up to 6.95 times that of the perfect flat surface. Under the condition of loading 70% of the ultimate stress and the same roughness, the fatigue life led by side-wall profile could be reduced to 1/25 of the textured surface. The obtained achievements promote an understanding for optimizing the fabrication process of resistive strain gauges as well as developing high-precision and long-life force sensors.

A Novel Prognostic Ferroptosis-Related Long Noncoding RNA Signature in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common primary malignancy of renal cancer in adults. Ferroptosis is critically associated with the prognosis of ccRCC. However, knowledge of long noncoding RNA- (lncRNA-) related ferroptosis that affects the prognosis of ccRCC is still insufficient. Using the LASSO regression, we created a risk model based on differentially expressed ferroptosis-related lncRNAs (FRLRS) in ccRCC. The analysis of Kaplan-Meier for survival, area under the curve (AUC) for diagnosis, nomogram for predicting overall survival, and gene expression for immune checkpoints were performed based on the screened independent prognostic factors. Nine lncRNAs were found to be associated with ccRCC prognosis. Furthermore, the prognostic AUC of the FRLRS signature was 0.78, demonstrating its usefulness in predicting ccRCC prognosis. The lncRNA risk model outperformed the standard clinical variables in predicting ccRCC prognosis. Finally, The Cancer Genome Atlas revealed that T cell functions, such as cytolytic activity, human leukocyte antigen activity, inflammation regulation, and type II interferon response coordination, are significantly different between two different risk levels of ccRCC. Immune checkpoints were also expressed differently in programmed cell death 1 receptor, inducible T cell costimulator, cytotoxic T-lymphocyte antigen-4, and leukocyte-associated immunoglobulin-like receptor 1. The nine FRLRS signature models may affect the prognosis of ccRCC.

Nickel nanoparticles affect the migration and invasion of HTR-8/SVneo cells by downregulating MMP2 through the PI3K/AKT pathway.

Proper migration and invasion of extravillous trophoblast cells into the endometrium in early gestation is essential for successful embryo implantation. The development of nanotechnology has led to the emergence of nickel nanoparticles (Ni NPs), for which attendant health concerns are widespread. Ni NPs are known to affect reproduction and be embryotoxic, but whether they affect the migration and invasion functions of trophoblast cells is unclear. We investigated the effects of Ni NPs on the migration and invasion of HTR-8/SVneo in extravillous trophoblast cells and explored the possible role of the PI3K/AKT/MMP2 signaling pathway in this regard. Results showed that the migration and invasion of cells was significantly inhibited by the exposure of Ni NPs. The protein and mRNA levels of PI3K/AKT/MMP2 signaling pathway were significantly reduced with the increase in Ni NPs concentration. The presence of the PI3K activator 740Y-P partially attenuated the inhibition of cell migration and invasion by Ni NPs, confirming the involvement of this pathway. Thus, Ni NPs inhibit migration and invasion of human trophoblast HTR-8/SVneo cells by downregulating the PI3K/AKT/MMP2 signaling pathway. This study is important for the development of safety evaluation criteria for Ni NPs.

Engineered Small Extracellular Vesicles as a FGL1/PD-L1 Dual-Targeting Delivery System for Alleviating Immune Rejection.

There is an urgent need for developing new immunosuppressive agents due to the toxicity of long-term use of broad immunosuppressive agents after organ transplantation. Comprehensive sample analysis revealed dysregulation of FGL1/LAG-3 and PD-L1/PD-1 immune checkpoints in allogeneic heart transplantation mice and clinical kidney transplant patients. In order to enhance these two immunosuppressive signal axes, a bioengineering strategy is developed to simultaneously display FGL1/PD-L1 (FP) on the surface of small extracellular vesicles (sEVs). Among various cell sources, FP sEVs derived from mesenchymal stem cells (MSCs) not only enriches FGL1/PD-L1 expression but also maintain the immunomodulatory properties of unmodified MSC sEVs. Next, it is confirmed that FGL1 and PD-L1 on sEVs are specifically bound to their receptors, LAG-3 and PD-1 on target cells. Importantly, FP sEVs significantly inhibite T cell activation and proliferation in vitro and a heart allograft model. Furthermore, FP sEVs encapsulated with low-dose FK506 (FP sEVs@FK506) exert stronger effects on inhibiting T cell proliferation, reducing CD8+ T cell density and cytokine production in the spleens and heart grafts, inducing regulatory T cells in lymph nodes, and extending graft survival. Taken together, dual-targeting sEVs have the potential to boost the immune inhibitory signalings in synergy and slow down transplant rejection.