Medical dilemma: Programmed death 1 blockade (sintilimab) therapy in patients suffering from tumours combined with psoriasis.

Tumour immunotherapy represented by immune checkpoint inhibitors (ICIs) has greatly improved the overall prognosis of patients with malignant tumours, and is regarded as an important breakthrough in the field of medicine in recent years. ICIs have gradually become the core of tumour therapy and are increasingly used in the clinic. In order to achieve early clinical prediction and management of immune-related adverse events (irAEs), it is still necessary to perform further research on the mechanisms, risk factors, and predictors of irAE occurrence in the future. Zhou et al describe the consultation of a patient with advanced gastric cancer combined with chronic plaque psoriasis. This case provides an important reference for the use of programmed cell death protein-1 (PD-1) inhibitors in patients of tumours combined with chronic plaque psoriasis. This case also highlights that screening of high-risk groups for irAEs is critical before applying PD-1 inhibitors to patients with chronic psoriasis combined with tumours. PD-1 inhibitors are new and potent antineoplastic agents that can cause serious immune-related adverse events such as toxic epidermal necrolysis release and psoriasis. Glucocorticosteroids are the first-line agents for irAEs. The incidence of rheumatic irAEs may be higher in reality, which will inevitably become a new challenge for rheumatologists and dermatologists.

Chemical shift assignments of PA2072 CHASE4 domain.

Diverse extracellular sensor domains enable cells to regulate their behavior, physiological processes, and interspecies interactions in response to environmental stimuli. These sensing mechanisms facilitate the ultimate adaptation of organisms to their surrounding conditions. Pseudomonas aeruginosa (PAO1) is a clinically significant opportunistic pathogen in hospital infection. The CHASE4 domain, a putative extracellular sensing module, is found in the N-terminus of GGDEF-EAL-containing PA2072, a transmembrane receptor from P. aeruginosa. However, the signal identification and sensing mechanism of monomeric PA2072 CHASE4 remains largely unknown. Here, we report backbone and side chain resonance assignments of PA2072 CHASE4 as a basis for studying the structural mechanism of CHASE4-mediated signal recognition.

Exploring the environmental contamination toxicity and potential carcinogenic pathways of perfluorinated and polyfluoroalkyl substances (PFAS): An integrated network toxicology and molecular docking strategy.

The objective of this study was to investigate the potential carcinogenic toxicity and mechanisms of PFAS in thyroid, renal, and testicular cancers base on network toxicology and molecular docking techniques. Structural modeling was performed to predict relevant toxicity information, and compounds and cancer-related targets were screened in multiple databases. The interaction of PFAS with three cancers and their key protein targets were explored by combining protein network analysis, enrichment analysis and molecular docking techniques. PFOA, PFOS, and PFHXS exhibited significant carcinogenic and cytotoxic effects. These compounds may induce cancer by mediating active oxygen metabolism and the transduction of phosphatidylinositol 3-kinase/protein kinase B signaling pathway through genes such as ALB, mTOR, MDM2, and ERBB2. Furthermore, the underlying toxic mechanisms may be linked to the pathways in cancer, chemical carcinogenesis through reactive oxygen species/receptor activation, and the FoxO signaling pathway. The results contribute to a comprehensive understanding of the effects of these environmental pollutants on genes, proteins, and metabolic pathways in living organisms. It revealed their toxicity mechanisms in inducing thyroid, renal, and testicular cancers, and provided a solid theoretical foundation for designing new environmental control strategies and drug screening initiatives. Additionally, the integrated application of network toxicology and molecular docking technology can enhance our understanding of the toxicity and mechanisms of unknown environmental pollutants, which is beneficial for protecting the environment and human health.

Sulfated polysaccharide from Antrodia cinnamomea mycelium cultured with zinc sulfate stimulates M1 polarization of macrophages through AKT/mTOR pathways.

Antrodia cinnamomea-derived sulfated polysaccharides (Ac-SPSs) have health benefits, but their yield is low. This study explores a strategy to increase Ac-SPS yield and elucidates the biofunctions of Ac-SPS. For this, A. cinnamomea mycelia were treated with zinc sulfate (ZnSO4) administered at 1, 10, and 100 µM. Firstly, functional assay indicated that ZnSO4 increases the Ac-SPS yield by 20 %-30 % compared with the control treatment. ZnSO4 engenders a population of middle-molecular-weight (~200 kDa) Ac-SPSs. Ac-SPS (ASZ-10) from A. cinnamomea treated with 10 µM ZnSO4 exhibits the best anti-proliferation ability against lung cancer A549 cells. Co-treatment of ASZ-10 does not inhibit lipopolysaccharide-induced inflammation but does induce M1-related markers of macrophage RAW264.7 cells. Secondly, immunomodulatory properties showed that ASZ-10 increases the expression of CD80+ and CD86+ in M-CSF-stimulated bone-marrow-derived macrophages. ASZ-10 induces M1 polarization through up-regulation of the AKT/mTOR pathway as confirmed by AKT and mTOR inhibitors eliminating ASZ-10-induced M1-like markers of macrophages. Through systemic chemical and functional analysis, this study shows that trace amounts (10 µM) of ZnSO4 increase Ac-SPS yield and it reveals that ASZ-10 exhibits anti-cancer activity and acts as a stimulator for M1 macrophages by stimulation of AKT and mTOR.

A Hypoxia-Decidual Macrophage Regulatory Axis in Normal Pregnancy and Spontaneous Miscarriage.

The significance of hypoxia at the maternal-fetal interface is proven to be self-explanatory in the context of pregnancy. During the first trimester, low oxygen conditions play a crucial role in processes such as angiogenesis, trophoblast invasion and differentiation, and immune regulation. Recently, there has been increasing research on decidual macrophages, which contribute to the maintenance of immune tolerance, placental and fetal vascular development, and spiral artery remodeling, to investigate the effects of hypoxia on their biological behaviors. On these grounds, this review describes the dynamic changes in oxygen levels at the maternal-fetal interface throughout gestation, summarizing current knowledge on how the hypoxic environment sustains a successful pregnancy by regulating retention, differentiation and efferocytosis of decidual macrophages. Additionally, we explore the relationship between spontaneous miscarriages and an abnormal hypoxia-macrophage axis, shedding light on the underlying mechanisms. However, further studies are essential to elucidate these pathways in greater detail and to develop targeted interventions that could improve pregnancy outcomes.

Targeting Ras-, Rho-, and Rab-family GTPases via a conserved cryptic pocket.

The family of Ras-like GTPases consists of over 150 different members, regulated by an even larger number of guanine exchange factors (GEFs) and GTPase-activating proteins (GAPs) that comprise cellular switch networks that govern cell motility, growth, polarity, protein trafficking, and gene expression. Efforts to develop selective small molecule probes and drugs for these proteins have been hampered by the high affinity of guanosine triphosphate (GTP) and lack of allosteric regulatory sites. This paradigm was recently challenged by the discovery of a cryptic allosteric pocket in the switch II region of K-Ras. Here, we ask whether similar pockets are present in GTPases beyond K-Ras. We systematically surveyed members of the Ras, Rho, and Rab family of GTPases and found that many GTPases exhibit targetable switch II pockets. Notable differences in the composition and conservation of key residues offer potential for the development of optimized inhibitors for many members of this previously undruggable family.

NSUN2 facilitates tenogenic differentiation of rat tendon-derived stem cells via m5C methylation of KLF2.

Introduction: Tendon-derived stem cells (TDSCs) play a critical role in tendon repair. N5-methylcytosine (m5C) is a key regulator of cellular processes such as differentiation. This study aimed to investigate the impact of m5C on TDSC differentiation and the underlying mechanism. Methods: TDSCs were isolated from rats and identified, and a tendon injury rat model was generated. Tenogenic differentiation in vitro was evaluated using Sirius red staining and quantitative real-time polymerase chain reaction, while that in vivo was assessed using immunohistochemistry and hematoxylin‒eosin staining. m5C methylation was analyzed using methylated RNA immunoprecipitation, dual-luciferase reporter assay, and RNA stability assay. Results: The results showed that m5C levels and NSUN2 expression were increased in TDSCs after tenogenic differentiation. Knockdown of NSUN2 inhibited m5C methylation of KLF2 and decreased its stability, which was recognized by YBX1. Moreover, interfering with KLF2 suppressed tenogenic differentiation of TDSCs, which could be abrogated by KLF2 overexpression. Additionally, TDSCs after NSUN2 overexpression contributed to ameliorating tendon injury in vivo. In conclusion, NSUN2 promotes tenogenic differentiation of TDSCs via m5C methylation of KLF2 and accelerates tendon repair. Conclusions: The findings suggest that overexpression of NSUN2 can stimulate the differentiation ability of TDSCs, which can be used in the treatment of tendinopathy.

Design and application of a prefabricated structure for large-span arch open-cut highway tunnels.

To enhance construction efficiency, improve lining quality, and reduce project costs, this study proposes a prefabricated arch structure scheme for large-span open-cut highway tunnels, specifically targeting the ongoing construction of an eight-lane open-cut tunnel on Chongqing's Xinsen Avenue. By establishing a finite element "load-structure" integrated calculation model and adopting an iterative analysis method, the impact of joint stiffness variations on internal force distribution was determined. Combined with long-term field monitoring and measurements, a thorough analysis was conducted on the performance of the prefabricated arch structure during different construction stages. The results indicate that after assembly into a ring, the structure undergoes a self-adaptive adjustment phase, during which the joints experience significant stress and deformation. Following top-layer backfilling and water level restoration, the axial force on the joints increases, while stress and deformation decrease, exerting a positive effect on the joint bearing capacity. From the construction period to post-opening operations, the stress variation experienced by the joints remains within a controllable range, demonstrating substantial safety margins. This fully validates the safety and reliability of the prefabricated arch structure scheme.

20(S)-Ginsenoside Rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting LAMC2-Modulated ABC transporters.

INTRODUCTION: Gemcitabine (GEM) is the first-line drug for pancreatic ductal adenocarcinoma (PDAC), but drug resistance severely restricts its chemotherapeutic efficacy. Laminin subunit γ2 (LAMC2) plays a crucial role in extracellular matrix formation in the development of GEM-resistance. However, the biological function of LAMC2 in GEM resistance and its molecular mechanisms are still unclear. 20(S)-Ginsenoside Rh2 (Rh2), one of the principal active components isolated from Ginseng Radix et Rhizoma, possesses strong anti-tumor effects. However, the effects of Rh2 on overcoming GEM resistance and its action mechanisms remain to be elucidated. OBJECTIVES: This study aimed to determine the efficacy of Rh2 on overcoming GEM resistance and to explore its underlying molecular mechanisms. METHODS: Clinical study, Western blotting, publicly available databasesand bioinformatic analyses were performed to investigate the protein expression of LAMC2 in the GEM-resistant PDAC patients and the acquired GEM-resistant PDAC cells. Then, the effects of Rh2 on overcoming the GEM resistance in PDAC were evaluated both in vitro and in vivo. Stable silencing or overexpression of LAMC2 in the GEM-resistant PDAC cells were established for validating the role of LAMC2 on Rh2 overcoming the GEM resistance in PDAC. RESULTS: The protein expression of LAMC2 was markedly increased in the GEM-resistant PDAC patient biopsies compared to the sensitive cases. The protein expression of LAMC2 was significantly higher in the acquired GEM-resistant PDAC cells than that in their parental cells. Rh2 enhanced the chemosensitivity of GEM in the GEM-resistant PDAC cells, and inhibited the tumor growth of Miapaca-2-GR cell-bearing mice and Krastm4TyjTrp53tm1BrnTg (Pdx1-cre/Esr1*) #Dam/J (KPC) mice. Rh2 effectively reversed the GEM resistance in Miapaca-2-GR and Capan-2-GR cells by inhibiting LAMC2 expression through regulating the ubiquitin-proteasome pathway. Knockdown of LAMC2 enhanced the chemosensitivity of GEM and the effects of Rh2 on overcoming the GEM resistance in PDAC cells and the orthotopic PDAC mouse model. Conversely, LAMC2 overexpression aggravated the chemoresistance of GEM and abolished the effects of Rh2 on overcoming GEM resistance via modulating ATP-binding cassette (ABC) transporters leading to the active GEM efflux. CONCLUSIONS: LAMC2 plays an important role in the GEM resistance in PDAC, and Rh2 is a potential adjuvant for overcoming the chemoresistance of GEM in PDAC.

Fibrosis to carcinogenesis: unveiling the causal dynamics between pulmonary fibrosis and lung cancer.

Background: Previous clinical evidence has shown a correlation between pulmonary fibrosis (PF) and lung cancer (LC), but their causal relationship remains unknown. Methods: This study utilized a bidirectional two-sample Mendelian randomization (MR) approach to explore the causal relationship between PF and LC, including its subtypes. Genetic data were obtained from the IEU and FinnGen Genome-Wide Association Studies (GWAS). SNPs with genome-wide significance were selected, and analyses were conducted using Inverse-Variance Weighted (IVW), MR Egger, and Weighted Median methods. The IVW results for various subtypes of lung cancer and PF were used in a meta-analysis to investigate the overall causal effect between PF and lung cancer. Sensitivity analysis was used for both MR and meta-analysis to investigate the robustness of the results. Results: The bidirectional MR analysis showed no significant causal relationship between PF and overall, LC or its subtypes, except for SCLC, which had a significant positive association (OR = 1.29, 95% CI 1.07-1.57, p = 0.009). The meta-analysis results indicated no overall causal effect (OR = 1.067, 95% CI: 0.952-1.195, P = 0.265, I² = 57.3%). In the reverse MR analysis, NSCLC and LUSC showed significant associations with PF (OR = 1.12, 95% CI 1.01-1.23, p = 0.028 and OR = 1.04, 95% CI 1.01-1.08, p = 0.012, respectively), while the meta-analysis results indicated no significant causal effect (OR = 1.006, 95% CI: 0.973-1.040, P = 0.734, I² = 55.9%). Sensitivity analyses indicated no evidence of horizontal pleiotropy or significant heterogeneity. Conclusion: This study suggests a potential causal relationship between PF and SCLC, as well as between NSCLC and LUSC with PF. However, the overall causal relationship between PF and LC was not statistically significant, possibly due to individual variability and other influencing factors. Further research using data from diverse populations is needed to validate these findings.

Study on Preclinical Safety and Toxic Mechanism of Human Umbilical Cord Mesenchymal Stem Cells in F344RG Rats.

Mesenchymal stem cells have made remarkable progress in recent years. Many studies have reported that human umbilical cord mesenchymal stem cells (hUC-MSCs) have no toxicity, but thromboembolism appeared in patients treated with hUC-MSCs. Therefore, people are still worried about the safety of clinical application. The study aims to determine the safety, potential toxic mechanism and biodistribution of hUC-MSCs. F344RG rats were given 5 or 50 million cells/kg of hUC-MSCs by single administration in compliance with Good Laboratory Practice standards. Standard toxicity was performed. RNA sequencing was then performed to explore the potential toxic mechanisms. In parallel, the biodistribution of hUC-MSCs was examined. The dose of 5 million cells/kg hUC-MSCs had no obvious toxicity on symptom, weight, food intake, hematology, serum biochemistry, urine biochemistry, cytokines, and histopathology. However, blood-tinged secretions in the urethral orifice and 20% mortality occurred at 50 million cells/kg. Disseminated intravascular coagulopathy (DIC) is the leading cause of death. hUC-MSCs significantly upregulated complement and coagulation cascade pathways gene expression, resulting in DIC. Besides, hUC-MSCs upregulated fibrinolytic system suppressor genes A2m, Serping1 and Serpinf2. hUC-MSCs survived in rats for less than 28 days, no hUC-MSC was detected in tissues outside the lungs. There was no toxicity in F344RG rats at 5 million cells/kg, but some toxicities were detected at 50 million cells/kg. hUC-MSCs significantly upregulated complement and coagulation cascade pathways, upregulated the expression of fibrinolytic system suppressor genes A2m, Serping1 and Serpinf2, to inhibit fibrinolytic system, caused DIC, which provided a new insight into the toxic mechanism of hUC-MSCs.

Glutamine metabolism promotes human trophoblast cell invasion via COL1A1 mediated by PI3K-AKT pathway.

Abnormal trophoblast invasion function is an important cause of recurrent spontaneous abortion (RSA). Recent research has revealed a connection between glutamine metabolism and RSA. However, the interplay between these three factors and their related mechanisms remains unclear. To address this issue, we collected villus tissues from 10 healthy women with induced abortion and from 10 women with RSA to detect glutamine metabolism. Then, the trophoblast cell line HTR-8/SVneo was used in vitro to explore the effect of glutamine metabolism on trophoblast cells invasion, which was tested by transwell assay. We found that the concentration of glutamine in the villi of the normal pregnancy group was significantly higher than that in the RSA group. Correspondingly, the expression levels of key enzymes involved in glutamine synthesis and catabolism, including glutamine synthetase and glutaminase, were significantly higher in the villi of the normal pregnancy group. Regarding trophoblast cells, glutamine markedly enhanced the proliferative and invasive abilities of HTR-8/SVneo cells. Additionally, collagen type I alpha 1 (COL1A1) was confirmed to be a downstream target of glutamine, and glutamine also activated the PI3K-AKT pathway in HTR-8/SVneo cells. These findings indicate that glutamine metabolism facilitates the invasion of trophoblasts by up-regulating COL1A1 expression through the activation of the PI3K-AKT pathway, but the specific mechanism of COL1A1 requires further study.

Regulating iron center by defective MoS2 for superior Fenton-like catalysis in water purification: The key role of surface interaction and superoxide radical in accelerating metal redox-cycling.

Transition metals exhibit high reactivity for Fenton-like catalysis in environmental remediation, but how to save consumption and reduce pollution is of great interest. In this study, rationally designed defect-engineered Fe@MoS2 (Fe@D-MoS2) was prepared by incorporating reactive iron onto structural defects generated from the chemical acid-etching, aiming to improve the energetic consumption of the catalyst in Fenton-like applications. Morphological and structural properties were elucidated in details, the Fenton-like reactivity was evaluated with five phenolic contaminants for oxidant activation, radical generation and environmental remediation. Compared to Fe@MoS2, Fe@D-MoS2 exhibited a 18.9-fold increase in phenol degradation (0.09 versus 1.79 min-1). Quenching experiments, electron paramagnetic resonance tests and electrochemical measurements revealed the dominant sulfate and superoxide radicals. Rendered by strong metal-substrate surface and electronic interactions from regulated chemical environment and coordination structure, the inert ≡ Fe(III) was reduced to the reactive ≡ Fe(II) accompanied by the ≡ Mo(IV) oxidation to ≡ Mo(V) in MoS2 lattice, with adjacent sulfur serving as the key electron transfer bridge. Therefore, this work shows that the incorporation of reactive centers is able to boost two-dimensional sulfide materials for environmental catalysis applications.

Deciphering microbial metabolic interactions and their implications for community dynamics in acid mine drainage sediments.

The microbially-mediated reduction processes have potential for the bioremediation of acid mine drainage (AMD), which represents a worldwide environment problem. However, we know little about the microbial interactions in anaerobic AMD sediments. Here we utilized genome-resolved metagenomics to uncover the nature of cooperative and competitive metabolic interactions in 90 AMD sediments across Southern China. Our analyses recovered well-represented prokaryotic communities through the reconstruction of 2625 population genomes. Functional analyses of these genomes revealed extensive metabolic handoffs which occurred more frequently in nitrogen metabolism than in sulfur metabolism, as well as stable functional redundancy across sediments resulting from populations with low genomic relatedness. Genome-scale metabolic modeling showed that metabolic competition promoted microbial co-occurrence relationships, suggesting that community assembly was dominated by habitat filtering in sediments. Notably, communities colonizing more extreme conditions tended to be highly competitive, which was typically accompanied with increased network complexity but decreased stability of the microbiome. Finally, our results demonstrated that heterotrophic Thermoplasmatota associated with ferric iron and sulfate reduction contributed most to the elevated levels of competition. Our study shed light on the cooperative and competitive metabolisms of microbiome in the hazardous AMD sediments, which may provide preliminary clues for the AMD bioremediation in the future.

The different paradigms of NK cell death in patients with severe trauma.

Lymphocyte decline, particularly the depletion of NK cells, is a prominent feature of immunosuppression following severe tissue injury, heightening the susceptibility of severe trauma patients to life-threatening infections. Previous research indicates that the reduction in the number of NK cells is closely associated with the process of cell death. Nonetheless, the precise mechanism of NK cell death remains unknown. Here, we discovered that following severe traumatic injury, NK cells undergo several cell death pathways, dominated by apoptosis and pyroptosis with coexistence of necrotic cell death, immunogenic cell death, ferroptosis, and autophagy. These NK cells with different paradigms of death have diverse cytokine expression profiles and diverse interactions with other immune cells. Further exploration revealed that hypoxia was strongly associated with this diverse paradigm of NK cell death. Detailed investigation of paradigms of cell death may help to enhance comprehension of lymphopenia post-severe trauma, to develop new strategy in preventing immunosuppression, and then to improve outcome for severe trauma population.

Long-term ambient ozone exposure and childhood asthma, rhinitis, eczema, and conjunctivitis: A multi-city study in China.

Evidence on the link of long-term exposure to ozone (O3) with childhood asthma, rhinitis, conjunctivitis and eczema is inconclusive. We did a population-based cross-sectional survey, including 177,888 children from 173 primary and middle schools in 14 Chinese cities. A satellite-based spatiotemporal model was employed to assess four-year average O3 exposure at both residential and school locations. Information on asthma, allergic rhinitis, eczema and conjunctivitis was collected by a standard questionnaire developed by the American Thoracic Society. We used generalized non-linear and linear mixed models to test the associations. We observed linear exposure-response associations between O3 and all outcomes. The odds ratios of doctor-diagnosed asthma, rhinitis, eczema, and conjunctivitis associated with per interquartile increment in home-school O3 concentration were 1.31 (95 % confidence interval [CI]: 1.28, 1.34), 1.25 (95 %CI: 1.23, 1.28), 1.19 (95 %CI: 1.16, 1.21), and 1.28 (95 %CI: 1.21, 1.34), respectively. Similar associations were observed for asthma-related outcomes including current asthma, wheeze, current wheeze, persistent phlegm, and persistent cough. Moreover, stronger associations were observed among children who were aged > 12 years, physically inactive, and exposed to higher temperature. In conclusion, long-term O3 exposure was associated with higher risks of asthma, allergic rhinitis, conjunctivitis and eczema in children.

Phosphoproteomic analysis reveals distinctive responses in Mangrovibacter phragmatis under high-salinity condition.

We conducted a thorough genome-wide investigation of protein phosphorylation in the halotolerant bacterium Mangrovibacter phragmitis (MPH) ASIOC01, using the Fe-IMAC enrichment method combined with tandem mass spectrometry under low- and high-salinity conditions. The phosphoproteome comprises 86 unique phosphorylated proteins, crucially involving pathways such as glycolysis/gluconeogenesis, the citrate cycle, chaperones, ribosomal proteins, and cell division. This study represents the first and most extensive investigation to-date comparing the bacterial phosphoproteome under different osmotic conditions using a gel-free approach. We identified 45 unique phosphoproteins in MPH cultured in media containing 1 % NaCl, and 33 exclusive phosphoproteins in MPH cultured in media containing 5 % NaCl. Eight phosphoproteins were detected in both growth conditions. Analysis of high-confidence phosphosites reveals that phosphorylation predominantly occurs on serine residues (52.3 %), followed by threonine (35.1 %) and tyrosine (12.6 %) residues. Interestingly, 34 % of the phosphopeptides display multiple phosphosites. Currently, prokaryotic phosphorylation site prediction platforms like MPSite and NetPhosBac 1.0 demonstrate an average prediction accuracy of only 21 % when applied to our dataset. Fourteen phosphoproteins did not yield matches when compared against dbPSP 2.0 (database of Phosphorylation Sites in Prokaryotes), indicating that these proteins may be novel phosphoproteins. These unique proteins undergoing phosphorylation under high salinity growth conditions potentially enhance their adaptive capabilities to environmental challenges.

Mechanism-guided engineering of a minimal biological particle for genome editing.

The widespread application of genome editing to treat or even cure disease requires the delivery of genome editors into the nucleus of target cells. Enveloped Delivery Vehicles (EDVs) are engineered virally-derived particles capable of packaging and delivering CRISPR-Cas9 ribonucleoproteins (RNPs). However, the presence of lentiviral genome encapsulation and replication components in EDVs has obscured the underlying delivery mechanism and precluded particle optimization. Here we show that Cas9 RNP nuclear delivery is independent of the native lentiviral capsid structure. Instead, EDV-mediated genome editing activity corresponds directly to the number of nuclear localization sequences on the Cas9 enzyme. EDV structural analysis using cryo-electron tomography and small molecule inhibitors guided the removal of ~80% of viral residues, creating a minimal EDV (miniEDV) that retains full RNP delivery capability. MiniEDVs are 25% smaller yet package equivalent amounts of Cas9 RNPs relative to the original EDVs, and demonstrated increased editing in cell lines and therapeutically-relevant primary human T cells. These results show that virally-derived particles can be streamlined to create efficacious genome editing delivery vehicles that could simplify production and manufacturing.