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The discovery of promising cytokines and clarification of their immunological mechanisms in controlling the intracellular fate of Mycobacterium tuberculosis (Mtb) are necessary to identify effective diagnostic biomarkers and therapeutic targets. To escape immune clearance, Mtb can manipulate and inhibit the normal host process of phagosome maturation. Phagosome maturation arrest by Mtb involves multiple effectors and much remains unknown about this important aspect of Mtb pathogenesis. In this study, we found that interleukin 16 (IL-16) is elevated in the serum samples of Tuberculosis (TB) patients and can serve as a specific target for treatment TB. There was a significant difference in IL-16 levels among active TB, latent TB infection (LTBI), and non-TB patients. This study first revealed that macrophages are the major source of IL-16 production in response to Mtb infection, and elucidated that IL-16 can promote Mtb intracellular survival by inhibiting phagosome maturation and suppressing the expression of Rev-erbα which can inhibit IL-10 secretion. The experiments using zebrafish larvae infected with M. marinum and mice challenged with H37Rv demonstrated that reducing IL-16 levels resulted in less severe pathology and improved survival, respectively. In conclusion, this study provided direct evidence that Mtb hijacks the host macrophages-derived interleukin 16 to enhance intracellular growth. It is suggesting the immunosuppressive role of IL-16 during Mtb infection, supporting IL-16 as a promising therapeutic target.

Underground gas storage (UGS) is a crucial method for mitigating seasonal fluctuations in natural gas consumption. However, in China, UGS is primarily achieved through the conversion of abandoned gas reservoirs with limited storage capacity. Radial jet drilling (RJD) is an effective technology for the secondary development of depleted reservoirs. The multiorifice nozzle is a critical component that can efficiently break rock and create radial holes to increase gas production. In this study, we investigate the impact of nozzle structure on energy conversion efficiency through numerical simulations and experiments. Additionally, we design a swirling multiorifice nozzle and verify its effectiveness in field applications. Our findings indicate that the nozzle pressure drop and vorticity are primarily generated at the acute angle of the orifices. The number of forward orifices is directly proportional to energy loss, while the discharge coefficient and hydraulic performance initially increase and then decrease. Swirling multiorifice nozzle have fewer backward orifices, so they have less energy loss and a larger discharge coefficient. It has achieved better rock-breaking results in field applications. In conclusion, this study provides theoretical guidance and technical support for the secondary development of gas storage.

Abstract A contribution to the engineering application of a proposed 500 kV fault current limiter (FCL) is presented. A new type of FCL composed of a highly coupled split reactor (HCSR) and fast switches is proposed. When the circuit breaker (CB) in series with the FCL in the 500 kV power system interrupts the limited fault current, the rate of rise of the recovery voltage (RRRV) reaches a value much higher than the rated value. Based on a simplified equivalent single‐phase circuit, the influence of the new FCL on the interruption procedure of the CB is simulated and discussed. The simulation results show that the high RRRV is caused by high‐frequency resonant oscillations between the HCSR and its parasite capacitance. Analysis indicates that when the reactance of the FCL is close to the short circuit reactance of the system, the RRRV will reach the highest value. To solve this issue, we proposed installing a shunt capacitor with the FCL. Simulation results showed that the RRRV under all fault modes could be restrained to below the rated value by introducing a certain shunt capacitor.

AbstractBackground Acute lymphoblastic leukaemia (ALL) is often characterized by broad clinical and biological heterogeneity, as well as recurrent genetic aberrations. Despite remarkable improvements in the treatment outcome in paediatric ALL over the past several decades, it remains a leading cause of morbidity and mortality among children. Cytokines have been extensively studied in haematologic diseases; however, the mechanisms by which cytokines contribute to ALL pathogenesis remain poorly understood.Methods IL-33 levels were measured by enzyme-linked immunosorbent assay (ELISA). IL1RL1 expression on ALL cell surface was accessed by flow cytometry. Expression of phosphorylated p38 MAPK, p38, pAKT, AKT and GAPDH were quantified by western blot. Cell survival signals were evaluated by apoptosis using flow cytometry.Results BM samples from ALL patients at diagnosis upregulated their cell surface expression of IL1RL1, and a higher interleukin (IL)-33 level in the serum was observed as compared to the healthy individuals. Moreover, exogenous IL-33 treatment significantly inhibited apoptosis by activating p38 mitogen-activated protein kinase (MAPK) and AKT pathway, while the inhibitor for p38 MAPK, SB203580, counteracted IL-33-induced anti-apoptosis via inactivation of p38 MAPK and AKT. Furthermore, IL-33 negatively regulates cyclin B1 protein level while increasing the expression of CDK1, with SB203580 inhibiting the effect.Conclusion Our study reveals an important role for IL-33/IL1RL1 axis in supporting ALL which may represent a novel treatment for paediatric patients.KEY MESSAGESBoth IL-33 and IL1RL1 levels are upregulated in primary ALL samples.IL-33 increased both p38 MAPK and AKT activation in ALL.IL-33 promotes survival and cell cycle progression of ALL cells via activating p38 MAPK.

Abstract In fractured tight reservoirs, the seepage capacity of the matrix is poor, and fluid migration mainly depends on matrix/fracture transfer. An accurate understanding of the matrix/fracture flow is the basis of well tests and numerical simulations for tight reservoirs. In this paper, the unsteady flow equation for tight reservoirs is deduced based on the boundary layer theory, which can reflect the effect of the dynamic threshold pressure gradient, and the theoretical flow equation is verified by seepage experiments. Based on the study of the flow equation, the approximate semi‐analytical solution of the matrix/fracture unsteady transfer shape factor and the transfer function for tight reservoirs are established considering the early stage of matrix/fracture transfer (pressure does not propagate to the matrix center) and the late stage of matrix/fracture transfer (pseudo‐steady state). The results show that the shape factor of the tight reservoir is mainly affected by three factors (minimum threshold pressure gradient, static boundary layer thickness, and sensitivity coefficient of the fluid boundary layer), and the theoretical curves show that the intermediate transfer enters the pseudo‐steady state when the dimensionless time reaches approximately 0.14. The higher the minimum threshold pressure gradient is, the larger the transfer shape factor. The larger the static boundary layer thickness is, the larger the transfer shape factor; additionally, the larger the sensitivity coefficient of the fluid boundary layer is, the faster the change rate of the shape factor. Finally, the transfer shape factor is applied to a well test interpretation. Examples prove that the fitting accuracy of the new curve type is improved by 34.2% compared with the curve type for the conventional well test interpretation method.

The theoretical research on the percolation mechanism and oil-water relative permeability of low-permeability oil reservoirs is the focus and hotspot of international researchers. Oil-water relative permeability is an important parameter that describes the characteristics of oil-water two-phase flow and is widely used in the dynamic analysis of development and numerical simulation technology in the reservoir. The traditional calculation method of oil-water relative permeability (i.e., the JBN method) is based on the Darcy flow law. When the velocity and the displacement pressure gradient do not follow the linear flow law, there are some errors in the results of oil-water relative permeability calculated by the JBN method. In this paper, the traditional JBN method is improved, and we establish a new processing method of experimental data for oil-water relative permeability considering the effects of nonlinear flow, capillary pressure, and gravity in tight oil reservoirs. The experiments on the flow characteristics of single-phase oil and oil-water relative permeability under nonsteady-state conditions were carried out. The flow velocity and displacement pressure gradient show nonlinear characteristics when single-phase oil is passed through a tight core. At the same time, when the air permeability decreases from 1.92×10−3 μm2 to 0.1×10−3 μm2, the nonlinear characteristics are becoming more and more obvious. Compared with the traditional JBN method, when the nonlinear flow characteristics are considered, the oil phase relative permeability increases, and the water phase relative permeability is slightly lower. If nonlinear flow characteristics are considered, when the water saturation increases from 0.605 to 0.699, the difference of oil phase relative permeability calculated by the JBN method and this method is gradually decreasing and, with the increase of water saturation, decreases from 0.0029 to 0.0001. In addition, the effects of capillary pressure, gravity, and the nonlinear flow coefficient on the oil-water relative permeability in tight oil reservoirs are studied. The capillary pressure also has a great influence on the relative permeability of the oil phase, and the relative permeability of the oil phase increases with the increase in capillary pressure. In the development process of the low-permeability reservoir, the seepage characteristics of each flow area are different, and the oil-water relative permeability is also different. Therefore, the research results play an important role in guiding the understanding of seepage characteristics of low permeability of tight oil reservoirs.

Trained monocytes and macrophages produce reactive oxygen species (ROS), which trigger antioxidative glutathione (GSH) response to buffer the rising ROS. However, whether and how the trained immunity is shaped by GSH synthesis remains unknown. Here, we report that β-glucan-trained macrophages from mice harboring a myeloid-specific deletion of the catalytic subunit of glutamate-cysteine ligase (Gclc) showed impaired GSH synthesis and decreased proinflammatory cytokine production in response to lipopolysaccharide challenge. Gclc deficiency compromised the activation of mammalian target of rapamycin-1 (mTOR) and expression of c-Myc transcription factors, abrogating the energy utilization and the metabolic reprogramming that allows β-glucan-trained macrophages to switch to glycolysis and glutaminolysis. Furthermore, Gclc deletion repressed effective H3K27me3 demethylation in the promoters of immunometabolic genes, such as Gls, Hk2, and Glut1, in β-glucan-trained macrophages by promoting the methyltransferase enhancer of zeste homolog 2 (EZH2). In vivo, myeloid-specific ablation of Gclc decreased the secretion of proinflammatory cytokines upon rechallenge with Candida albicans and these animals were less protected against the infection, compared with control littermates. Moreover, pharmacological inhibition of EZH2 enhanced the trained immunity response against Candida infection in Gclc-deficient mouse and human peripheral blood mononuclear cells treated with GCLC inhibitor buthionine sulfoximine (BSO). Thus, antioxidative GSH synthesis supports an environment conducive to β-glucan-induced metabolic and epigenetic reprogramming in trained immunity, allowing exploration of its functional consequences in autoimmune or inflammatory disease.

Trained immunity, induced by β-glucan in monocytes, is mediated by activating metabolic pathways that result in epigenetic rewiring of cellular functional programs; however, molecular mechanisms underlying these changes remain unclear. Here, we report a key immunometabolic and epigenetic pathway mediated by the miR–9-5p-isocitrate dehydrogenase 3α (IDH3α) axis in trained immunity. We found that β-glucan–trained miR–9-5p–/– monocytes showed decreased IL-1β, IL-6, and TNF-α production after LPS stimulation. Trained miR–9-5p–/– mice produced decreased levels of proinflammatory cytokines upon rechallenge in vivo and had worse protection against Candida albicans infection. miR–9-5p targeted IDH3α and reduced α-ketoglutarate (α-KG) levels to stabilize HIF-1α, which promoted glycolysis. Accumulating succinate and fumarate via miR–9-5p action integrated immunometabolic circuits to induce histone modifications by inhibiting KDM5 demethylases. β-Glucan–trained monocytes exhibited low IDH3α levels, and IDH3α overexpression blocked the induction of trained immunity by monocytes. Monocytes with IDH3α variants from autosomal recessive retinitis pigmentosa patients showed a trained immunity phenotype at immunometabolic and epigenetic levels. These findings suggest that miR–9-5p and IDH3α act as critical metabolic and epigenetic switches in trained immunity.

Ischemic stroke has been reported to cause significant changes to memory, thinking, and behavior. Intriguingly, recently reported studies have indicated the association of Trimethylamine N-oxide (TMAO) with the acute phase of ischemic stroke. However, the comprehensive underlying mechanism remained unknown. The objective of the present study was to investigate the association between TMAO and recovery of neurological function after ischemic stroke. For this purpose, a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model was established and treated with TMAO or/and sh-ALK5, followed by the neurological function evaluation. Behaviors of rats were observed through staircase and cylinder tests. Moreover, the expression of Smurf2 and ALK5 was detected by immunohistochemistry while expression of GFAP, Neurocan, and Phosphacan in brain tissues was determined by immunofluorescence. Thereafter, gain- and loss-of-function assays in astrocytes, the proliferation, viability, and migration were evaluated by the EdU, CCK-8, and Transwell assays. Besides, Smurf2 mRNA expression was determined by the RT-qPCR, whereas, Smurf2, ALK5, GFAP, Neurocan, and Phosphacan expression was evaluated by the Western blotting. Finally, the interaction of Smurf2 with ALK5 and ALK5 ubiquitination was assessed by the co-immunoprecipitation. Notably, our results showed that TMAO promoted the proliferation of reactive astrocyte and formation of glial scar in MCAO/R rats. However, this effect was abolished by the Smurf2 overexpression or ALK5 silencing. We further found that TMAO upregulated the ALK5 expression by inhibiting the ubiquitination role of Smurf2. Overexpression of ALK5 reversed the inhibitory effect of Smurf2 on astrocyte proliferation, migration, and viability. Collectively, our work identifies the evolutionarily TMAO/Smurf2/ALK5 signaling as a major genetic factor in the control of reactive astrocyte proliferation and glial scar formation in ischemic stroke, thus laying a theoretical foundation for the identification of ischemic stroke.

Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of immature myeloid blasts in the bone marrow (BM). Cytokine provide signals for leukemia cells to improve their survival in the BM microenvironment. Previously, we identified interleukin-33 (IL-33) as a promoter of cell survival in a human AML cell line and primary mouse leukemia cells. In this study, we report that the cell surface expression of IL-33–specific receptor, Interleukin 1 Receptor Like 1 (IL1RL1), is elevated in BM cells from AML patients at diagnosis, and the serum level of IL-33 in AML patients is higher than that of healthy donor controls. Moreover, IL-33 levels are found to be positively associated with IL-6 levels in pediatric patients with AML. In vitro, IL-33 treatment increased IL-6 mRNA expression and protein level in BM and peripheral blood (PB) cells from AML patients. Evidence was also provided that IL-33 inhibits cell apoptosis by activating p38 mitogen-activated protein kinase (MAPK) pathway using human AML cell line and AML patient samples. Finally, we confirmed that IL-33 activated IL-6 expression in a manner that required p38 MAPK pathway using clinical AML samples. Taken together, we identified a potential mechanism of IL-33–mediated survival involving p38 MAPK in pediatric AML patients that would facilitate future drug development.

Targeting of Mycobacterium tuberculosis (MTB) latent antigens comprises a crucial strategy for the development of alternative tuberculosis (TB) vaccine(s) that protects against TB reactivation. Here, we generated a multistage DNA vaccine, A39, containing the early antigens Ag85A and Rv3425 as well as the latency-associated protein Rv2029c, which conferred protective immunity in a pre-exposure mouse model. Moreover, administration of the A39 vaccination after MTB exposure inhibited reactivation and resulted in significantly lower bacterial loads in the lungs and spleen of mice, compared to those in the control population. Subsequently, we investigated the effect of Rv2029c on innate immunity and characterized the molecular details of the interaction of this protein with the host via iTRAQ proteomic and biochemical assay analyses. Rv2029c activated macrophages, triggered the production of pro-inflammatory cytokines, and promoted toll-like receptor/mitogen-activated protein kinase (TLR/MAPK)-dependent macrophage apoptosis. Furthermore, Rv2029c treatment enhanced the ability of Mycobacterium bovis Bacillus Calmette-Guérin (BCG)-infected macrophages to present antigens to CD4+ T cells in vitro, which correlated with an increase in MHC-II expression. Lastly, Rv2029c-treated macrophages activated T cells, effectively polarized CD4+ and CD8+ T cells to secrete IFN-γ and IL-2, and specifically expanded a population of CD44highCD62LlowCD4+/CD8+ effector/memory cells, indicating that Rv2029c, as a specific recall antigen, contributes to Th1 polarization in T cell immunity. These results suggest that Rv2029c and A39 comprise promising targets for the development of next-generation clinical TB therapeutic vaccines.

As one of the key technologies to solve the problem of high short-circuit current, the fault current limiter (FCL) has become a research hotspot in China and abroad. The overvoltage and protection measures of the FCL are the key technologies for its application. Therefore, this paper studies the lightning intruding overvoltage and protection measures for a 500 kV FCL based on a high coupled split reactor (HCSR). Firstly, according to the main topology of the system and the 500 kV HCSR-FCL structure, the lightning intruding overvoltage simulation model of the 500 kV station, including the nearby transmission lines, is established on the PSCAD (Power Systems Computer Aided Design) program. Secondly, the lightning overvoltage of the equipment in the station and the components of the HCSR-FCL are simulated and analyzed when the transmission lines nearby are subjected to lightning shielding failure and back flashover. Meanwhile, the influence of the HCSR-FCL on the lightning overvoltage of the equipment in the station are compared and analyzed before and after the HCSR-FCL is installed. The simulation results show that the overvoltage of the equipment in the station and the components of the HCSR-FCL is more serious when the shielding failure occurs in the transmission lines nearby. The HCSR-FCL can reduce the lightning overvoltage of the equipment in the station, but the maximum inter-terminal and inter-arm lightning overvoltage of the HCSR can reach 1064 kV and 790 kV, respectively, under the current limiting state and the current sharing state. Finally, methods of increasing the arresters on the transmission lines side of the HCSR-FCL and shunt capacitor between each module of the HCSR-FCL are proposed to reduce the lightning overvoltage. The lightning impulse withstand voltage of each component of the HCSR is also proposed: The inter-terminal lightning impulse withstand voltage of HCSR is 170 kV. The inter-arm lightning impulse withstand voltage of HCSR is 200 kV. The terminal-to-ground lightning impulse withstand voltage of the HCSR-FCL is 1550 kV.

TLR2-dependent cellular signaling in Mycobacterium tuberculosis-infected macrophages causes apoptosis and inhibits class II major histocompatibility complex (MHC-II) molecules antigen processing, leading to evasion of surveillance. Mycobacterium tuberculosis (Mtb) lipoproteins are an important class of Toll-like receptor (TLR) ligand, and identified as specific components that mediate these effects. In this study, we identified and characterized Mtb lipoprotein Rv1016c (lpqT) as a cell wall associated-protein that was exposed on the cell surface and enhanced the survival of recombinants M. smegmatis_Rv1016c under stress conditions. We found that Rv1016c lipoprotein was a novel TLR2 ligand and able to induce macrophage apoptosis in a both dose- and time-dependent manner. Additionally, apoptosis induced by Rv1016c was reserved in THP-1 cells blocked with anti-TLR-2 Abs or in TLR2-/- mouse macrophages, indicating that Rv1016c-induced apoptosis is dependent on TLR2. Moreover, we demonstrated that Rv1016c lipoprotein inhibited IFN-γ-induced MHC-II expression and processing of soluble antigens in a TLR2 dependent manner. Class II transactivator (CIITA) regulates MHC II expression. In this context, Rv1016c lipoprotein diminished IFN-γ-induced expression of CIITA IV through TLR2 and MAPK Signaling. TLR2-dependent apoptosis and inhibition of MHC-II Ag processing induced by Rv1016c during mycobacteria infection may promote the release of residual bacilli from apoptotic cells and decrease recognition by CD4+ T cells. These mechanisms may allow intracellular Mtb to evade immune surveillance and maintain chronic infection.

Abstract Background In the era of immunotherapy, neoadjuvant immunochemotherapy (NAIC) for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC) is used clinically but lacks of high‐level clinical evidence. This study aimed to compare the safety and long‐term efficacy of NAIC followed by minimally invasive esophagectomy (MIE) with those of neoadjuvant chemotherapy (NAC) followed by MIE. Methods A prospective, single‐center, open‐label, randomized phase III clinical trial was conducted at Henan Cancer Hospital, Zhengzhou, China. Patients were randomly assigned to receive either neoadjuvant toripalimab (240 mg) plus paclitaxel (175 mg/m2) + cisplatin (75 mg/m2) (toripalimab group) or paclitaxel + cisplatin alone (chemotherapy group) every 3 weeks for 2 cycles. After surgery, the toripalimab group received toripalimab (240 mg every 3 weeks for up to 6 months). The primary endpoint was event‐free survival (EFS). The pathological complete response (pCR) and overall survival (OS) were key secondary endpoints. Adverse events (AEs) and quality of life were also assessed. Results Between May 15, 2020 and August 13, 2021, 252 ESCC patients ranging from T1N1‐3M0 to T2‐3N0‐3M0 were enrolled for interim analysis, with 127 in the toripalimab group and 125 in the chemotherapy group. The 1‐year EFS rate was 77.9% in the toripalimab group compared to 64.3% in the chemotherapy group (hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.39 to 1.00; P = 0.05). The 1‐year OS rates were 94.1% and 83.0% in the toripalimab and chemotherapy groups, respectively (HR = 0.48; 95% CI = 0.24 to 0.97; P = 0.037). The patients in the toripalimab group had a higher pCR rate (18.6% vs. 4.6%; P = 0.001). The rates of postoperative Clavien‐Dindo grade IIIb or higher morbidity were 9.8% in the toripalimab group and 6.8% in the chemotherapy group, with no significant difference observed (P = 0.460). The rates of grade 3 or 4 treatment‐related AEs did not differ between the two groups (12.5% versus 12.4%). Conclusions The interim results of this ongoing trial showed that in resectable ESCC, the addition of perioperative toripalimab to NAC is safe, may improve OS and might change the standard treatment in the future.

Abstract Background&Aims Gastrointestinal (GI) cancers, including gastric, liver, esophageal, pancreatic, and colorectal cancers, represent significant global health burdens. Emerging evidence suggests that dietary patterns, particularly their inflammatory and oxidative properties, may influence cancer risk. The Dietary Inflammatory Index (DII) and Dietary Oxidative Balance Score (DOBS) assess the inflammatory and oxidative effects of diets, respectively. This study aims to explore the association between DII, DOBS, and the combined risk of GI cancers, and investigates the potential mediating roles of serum albumin and red cell distribution width (RDW). Methods Data from 26,320 participants in the NHANES 2005–2018 cycles were analyzed. DII was calculated based on 28 dietary components, and DOBS included 17 nutrients (3 pro-oxidants and 14 antioxidants). Logistic regression models assessed the associations between DII, DOBS, and GI cancers. Restricted cubic spline (RCS) models examined dose-response relationships. Mediation analysis evaluated the roles of serum albumin and RDW. Subgroup analyses explored interactions with demographic and health-related factors. Results Higher DII was associated with increased GI cancer risk (OR: 1.26, 95% CI: 1.07–1.49 per unit increase), while higher DOBS was associated with reduced risk (OR: 0.90, 95% CI: 0.76–0.99 per unit increase). RCS analysis indicated a significant nonlinear relationship between DII and GI cancer risk. Serum albumin and RDW partially mediated the associations between DII, DOBS, and GI cancers. Subgroup analyses showed stronger associations for DII among certain demographics, and significant interactions were found between DII and BMI. For DOBS, significant interactions were observed with age and BMI. Conclusion This study reveals significant associations between dietary inflammatory and oxidative balance scores and GI cancer risk. Higher DII is linked to increased risk, while higher DOBS is protective. The mediating roles of serum albumin and RDW provide insights into underlying mechanisms. These findings underscore the potential of dietary modifications in GI cancer prevention and management, emphasizing the importance of anti-inflammatory and antioxidant-rich diets.

Abstract Background Febrile respiratory syndrome (FRS) is often associated with viral infections. The aim of this study was to identify the viral pathogens responsible for FRS in Liaoning Province, China. Methods We tested eight respiratory viruses, namely, influenza virus (IFV), rhinovirus (RV), human adenovirus (HAdV), human bocavirus (HBoV), human parainfluenza virus (HPIV), human coronavirus (HCoV), respiratory syncytial virus (RSV), and human metapneumovirus (HMPV), using reverse transcription-polymerase chain reaction (RT-PCR). Statistical analyses were performed using SPSS version 25.0, and the data were plotted using RStudio 4.2.1 software. Results IFV was the most frequently identified pathogen, followed by RV, HAdV, HBoV, HPIV, HCoV, RSV, and HMPV. RSV/HBoV coinfection occurred most frequently among the mixed cases. The rate of respiratory virus detection was highest in children under one year of age and decreased significantly with age. Seasonal trends showed a peak in virus detection during the winter months. Conclusions IFV is the leading cause of FRS in Liaoning Province, China, with single-virus infections prevailing over coinfections. Observations indicate a differential virus detection rate across age groups and seasons, highlighting the need for focused preventive strategies to mitigate the transmission of respiratory viruses, particularly among susceptible populations in the colder season.

Abstract Lipid nanoparticles (LNPs) have proven themselves as transformative actors in chimeric antigen receptor (CAR) T cell therapy, surpassing traditional methods and addressing challenges like immunogenicity, reduced toxicity, and improved safety. Promising preclinical results signal a shift toward safer and more effective CAR T cell treatments. Ongoing research aims to validate these findings in clinical trials, marking a new era guided by LNPs utility in CAR therapy. Herein, we explore the preference for LNPs over traditional methods, highlighting the versatility of LNPs and their effective delivery of nucleic acids. Additionally, we address key challenges in clinical considerations, heralding a new era in CAR T cell therapy. Graphical Abstract