Phosphoproteomic Analysis Indicates Phosphorylated Proteins in Response to Postharvest Blueberries Fruit Softening during Shelf Life.

Postharvest blueberry fruit is prone to softening. Protein phosphorylation is an important post-translational modification that was involved in fruit softening. However, little is known about protein phosphorylation in postharvest blueberry fruit softening. The firmness, the apparent morphology, and cell structures of blueberry fruit were changed. As the decay rate of postharvest blueberry fruit increased, the soluble solid and titrable acid contents decreased significantly. Phosphoproteomic sequencing results showed that there were 4100 phosphorylated peptides, 5635 phosphorylated sites, and 1437 phosphorylated proteins and showed significant differences on 0 and 8 d. The GO database and KEGG pathway results indicated that these phosphorylated proteins were mainly involved in "biological process", "molecular function", "plant hormone signal transduction", and "metabolic pathways". Besides, a number of phosphorylated proteins were found in cell wall metabolism, plant hormone signaling, primary metabolism, energy metabolism, membrane and transport, ubiquitination-based proteins, and other metabolisms.

Influences of Pre-Existing Fissure Angles and Bridge Angles on Concrete Tensile Failure Characteristics: Insights from Meshless Numerical Simulations.

The existence of cracks is a key factor affecting the strength of concrete. However, traditional numerical methods still have some limitations in the simulation of crack growth in fissured concrete structures. Based on this background, the numerical treatment method of particle failure in smoothed particle hydrodynamics (SPH) is proposed, and the generation method for concrete meso-structures under the smoothed particle hydrodynamics (SPH) framework is developed. The concrete meso-models under different pre-existing micro-fissure inclinations and bridge angles (the inner tip line of the double pre-existing micro-fissure is defined as a bridge, and the angle between the bridge and the horizontal direction is defined as the bridge angle) were established, and numerical simulations of the crack propagation processes of concrete structures under tensile stress were carried out. The main findings were as follows: The concrete meso-structures and the pre-existing micro-fissures all have great impacts on the final failure modes of concrete. The stress-strain curve of the concrete model presents four typical stages. Finally, the crack initiation and propagation mechanisms of fissured concrete are discussed, and the application of smoothed particle hydrodynamics (SPH) in crack simulations of fissured concrete is prospected.

Exploring the role of learning goal orientation, instructor reputation, parasocial interaction, and tutor intervention in university students' MOOC retention: A TAM-TRA based examination.

While MOOC platforms allow universities to implement various strategies such as brand promotion and student recruitment, the alarmingly low retention rate suggests a need to explore the critical factors that influence students' course retention. So far, studies on MOOC platforms focus either on the students' individual factors (i.e., students' personal factors such as perceived value) or situational factors (i.e., external influences shaping students' behavior, such as system quality) for students' learning, thus lacking a complete view of those determinant factors. This study integrates the TAM model with the TRA model to analyze the roles of three important antecedents (learning goal orientation; LGO, instructor reputation; IR, & parasocial interaction; PI) on university students' perceived value (PU) and learning attitude (LA), two critical predictors of MOOC retention (CR). Using data from an online survey of 449 Chinese university students, the hypothesis model was tested using PLS. We found that LGO, IR, and PI each positively affect PU; LGO, IR, and PI each positively affect LA; PU and LA each positively influence course retention (CR), with each impact enhanced by tutor intervention (TI). The theoretical and practical implications of such findings are presented.

Advances in the mechanism of action of short-chain fatty acids in psoriasis.

Psoriasis is a prevalent chronic inflammatory and immunological disorder. Its lesions are present as scaly erythema or plaques. Disruptions in the body's immune system play a significant role in developing psoriasis. Recent evidence suggests a potential role of the gut microbiome in autoimmune diseases. Short-chain fatty acids (SCFAs) are the primary metabolites created by gut microbes and play a crucial fuction in autoimmunity. SCFAs act on various cells by mediating signaling to participate in host physiological and pathological processes. These processes encompass body metabolism, maintenance of intestinal barrier function, and immune system modulation. SCFAs can regulate immune cells to enhance the body's immune function, potentially influencing the prevention and treatment of psoriasis. However, the mechanisms underlying the role of SCFAs in psoriasis remain incompletely understood. This paper examines the relationship between SCFAs and psoriasis, elucidating how SCFAs influence the immune system, inflammatory response, and gut barrier in psoriasis. According to the study, in psoriasis, SCFAs have been shown to regulate neutrophils, macrophages, and dendritic cells in the adaptive immune system, as well as T and B cells in the innate immune system. Additionally, we explore the role of SCFAs in psoriasis by maintaining intestinal barrier function, restoring intestinal ecological homeostasis, and investigating the potential therapeutic benefits of SCFAs for psoriasis.

Gestational exposure to the great Chinese famine: early life undernutrition impact on prostatic hyperplasia in adulthood.

Introduction: Benign prostatic hyperplasia (BPH) is a frequent illness in aged men that impacts their quality of life; early childhood exposure to famines may have long-term effects on the chance of developing BPH. The aim of this study is to investigate the relationship between early-life famine exposure and benign prostatic hyperplasia (BPH) risk in Chinese men born during 1959-1961. Methods: We used medical records from a large, comprehensive hospital to screen people born in China during the years of famine (1959-1961). Birthplaces were identified as indicators of famine exposure status. In the time window between 2017 and 2022, people born during the famine years who had prostatic ultrasonic examinations were selected, and their medical records were retrieved from the database. Univariate and multivariate logistic regression analyses investigated the relationship between famine exposure and BPH risk. Results: A total of 3,009 subjects were included in this study. Patients with heavy famine exposure had older age, shorter height, lighter weight, lower cholesterol, lower uric acid (UA), lower aspartate aminotransferase (ALT), and a higher incidence of BPH than those with light famine exposure (all p < 0.05). Univariate logistic regression showed that BPH was positively related to famine exposure, age, height, weight, and body mass index (BMI) but negatively related to UA (all p < 0.05). Multivariate logistic regression showed that age and famine exposure were still independent risk factors (p < 0.05), while UA was an independent protective factor for BPH (p < 0.05). Heavy famine exposure increased the risk of BPH (adjusted OR = 1.214, 95% CI = 1.05-1.467, p = 0.045). Conclusions and recommendation: Famine and malnutrition exposure during early life may be independent risk factors for BPH in Chinese adults. This relationship provides additional evidence to support the fetal origins of adult diseases and offers clues for the pathological mechanisms of BPH.

Discovery of Biphenyl Derivatives to Target Hsp70-Bim Protein-Protein Interaction in Chronic Myeloid Leukemia by Scaffold Hopping Strategy.

Hsp70-Bim protein-protein interaction (PPI) is the most recently identified specific target in chronic myeloid leukemia (CML) therapy. Herein, we developed a new class of Hsp70-Bim PPI inhibitors via scaffold hopping of S1g-10, the most potent Hsp70-Bim PPI inhibitor thus far. Through structure-activity relationship (SAR) study, we obtained a biphenyl scaffold compound JL-15 with a 5.6-fold improvement in Hsp70-Bim PPI suppression (Kd = 123 vs 688 nM) and a 4-fold improvement in water solubility (29.42 vs 7.19 µg/mL) compared to S1g-10. It maintains comparable apoptosis induction capability with S1g-10 against both TKI-sensitive and TKI-resistant CML cell lines in an Hsp70-Bim-dependent manner. Additionally, through SAR, 1H-15N TRSOY-NMR, and molecular docking, we revealed that Lys319 is a "hot spot" in the Hsp70-Bim PPI interface. Collectively, these results provide a novel chemical scaffold and structural insights for the rational design of Hsp70-Bim PPI inhibitors.

Highly Efficient Photoelectrochemical Alkene Epoxidation on a Dye-Sensitized Photoanode.

In photoelectrochemical (PEC) cells, selective oxidation of organic substrates coupled with hydrogen evolution represents a promising approach for value-added chemical production and solar energy conversion. In this study, we report on PEC epoxidation of alkenes at a ruthenium dye-sensitized photoanode in a CH3CN/H2O mixed solvent with LiBr as a mediator and water as the oxygen source. The dye-sensitized photoanode was found to exhibit significant advantages in the simultaneous improvement of charge separation and suppression of charge recombination. First, LiBr as a redox mediator plays a critical role in charge separation, leading to an excellent excited electron injection efficiency of 95% and a high dye regeneration efficiency of 87%. Second, the predominant charge recombination pathway on the dye-sensitized photoanode is efficiently blocked by the reaction between alkene and the in situ generated bromine oxidant. As a result, the current system achieved a remarkable photocurrent density of over 4 mA cm-2 with a record-high incident photo-to-current efficiency (IPCE) of 51% and extraordinary selectivity of up to 99% for the epoxidation of a wide range of alkenes. Meanwhile, nearly 100% Faradaic efficiency for hydrogen evolution was obtained. The performance shown here exceeds that obtained by metal oxide-based semiconductor photoanodes under comparable conditions, demonstrating the great potential of dye-sensitized photoelectrodes for organic synthesis owing to their diversity and tunability.

Protein absorption in the zebrafish gut is regulated by interactions between lysosome rich enterocytes and the microbiome.

Dietary protein absorption in neonatal mammals and fishes relies on the function of a specialized and conserved population of highly absorptive lysosome rich enterocytes (LREs). The gut microbiome has been shown to enhance absorption of nutrients, such as lipids, by intestinal epithelial cells. However, whether protein absorption is also affected by the gut microbiome is poorly understood. Here, we investigate connections between protein absorption and microbes in the zebrafish gut. Using live microscopy-based quantitative assays, we find that microbes slow the pace of protein uptake and degradation in LREs. While microbes do not affect the number of absorbing LRE cells, microbes lower the expression of endocytic and protein digestion machinery in LREs. Using transgene assisted cell isolation and single cell RNA-sequencing, we characterize all intestinal cells that take up dietary protein. We find that microbes affect expression of bacteria-sensing and metabolic pathways in LREs, and that some secretory cell types also take up protein and share components of protein uptake and digestion machinery with LREs. Using custom-formulated diets, we investigated the influence of diet and LRE activity on the gut microbiome. Impaired protein uptake activity in LREs, along with a protein-deficient diet, alters the microbial community and leads to increased abundance of bacterial genera that have the capacity to reduce protein uptake in LREs. Together, these results reveal that diet-dependent reciprocal interactions between LREs and the gut microbiome regulate protein absorption.

Reprogrammed IDO-Induced Immunosuppressive Microenvironment Synergizes with Immunogenic Magnetothermodynamics for Improved Cancer Therapy.

Indoleamine 2,3-dioxygenase (IDO), highly expressed in hepatocellular carcinoma (HCC), plays a pivotal role in creating an immune-suppressive tumor microenvironment. Inhibiting IDO activity has emerged as a promising immunotherapeutic strategy; however, the delivery of IDO inhibitors to the tumor site is constrained, limiting their therapeutic efficacy. In this study, we developed a magnetic vortex nanodelivery system for the targeted delivery of the IDO inhibitor NLG919, integrated with magnetic hyperthermia therapy to reverse the immune-suppressive microenvironment of liver cancer and inhibit tumor growth. This system comprises thermoresponsive polyethylenimine-coated ferrimagnetic vortex-domain iron oxide nanorings (PI-FVIOs) loaded with NLG919 (NLG919/PI-FVIOs). Under thermal effects, NLG919 can be precisely released from the delivery system, counteracting IDO-mediated immune suppression and synergizing with NLG919/PI-FVIOs-mediated magnetothermodynamic (MTD) therapy-induced immunogenic cell death (ICD), resulting in effective HCC suppression. In vivo studies demonstrate that this combination therapy significantly inhibits tumor growth and metastasis by enhancing the accumulation of cytotoxic T lymphocytes and suppressing regulatory T cells within the tumor. Overall, our findings reveal that NLG919/PI-FVIOs can induce a potent antitumor immune response by disrupting the IDO pathway and activating the ICD, offering a promising therapeutic avenue for HCC treatment.

Nanomaterials in modulating tumor-associated macrophages and enhancing immunotherapy.

Tumor-associated macrophages (TAMs) are predominantly present in the tumor microenvironment (TME) and play a crucial role in shaping the efficacy of tumor immunotherapy. These TAMs primarily exhibit a tumor-promoting M2-like phenotype, which is associated with the suppression of immune responses and facilitation of tumor progression. Interestingly, recent research has highlighted the potential of repolarizing TAMs from an M2 to a pro-inflammatory M1 status-a shift that has shown promise in impeding tumor growth and enhancing immune responsiveness. This concept is particularly intriguing as it offers a new dimension to cancer therapy by targeting the tumor microenvironment, which is a significant departure from traditional approaches that focus solely on tumor cells. However, the clinical application of TAM-modulating agents is often challenged by issues such as insufficient tumor accumulation and off-target effects, limiting their effectiveness and safety. In this regard, nanomaterials have emerged as a novel solution. They serve a dual role: as delivery vehicles that can enhance the accumulation of therapeutic agents in the tumor site and as TAM-modulators. This dual functionality of nanomaterials is a significant advancement as it addresses the key limitations of current TAM-modulating strategies and opens up new avenues for more efficient and targeted therapies. This review provides a comprehensive overview of the latest mechanisms and strategies involving nanomaterials in modulating macrophage polarization within the TME. It delves into the intricate interactions between nanomaterials and macrophages, elucidating how these interactions can be exploited to drive macrophage polarization towards a phenotype that is more conducive to anti-tumor immunity. Additionally, the review explores the burgeoning field of TAM-associated nanomedicines in combination with tumor immunotherapy. This combination approach is particularly promising as it leverages the strengths of both nanomedicine and immunotherapy, potentially leading to synergistic effects in combating cancer.

Strong interactions through the highly polar "Early-Late" metal-metal bonds enable single-atom catalysts good durability and superior bifunctional ORR/OER activity.

Simultaneously enhancing the durability and catalytic performance of metal-nitrogen-carbon (M-Nx-C) single-atom catalysts is critical to boost oxygen electrocatalysis for energy conversion and storage, yet it remains a grand challenge. Herein, through the combination of early and late metals, we proposed to enhance the stability and tune the catalytic activity of M-Nx-C SACs in oxygen electrocatalysis by their strong interaction with the M2'C-type MXene substrate. Our density functional theory (DFT) computations revealed that the strong interaction between "early-late" metal-metal bonds significantly improves thermal and electrochemical stability. Due to considerable charge transfer and shift of the d-band center, the electronic properties of these SACs can be extensively modified, thereby optimizing their adsorption strength with oxygenated intermediates and achieving eight promising bifunctional catalysts for ORR/OER with low overpotentials. More importantly, the constant-potential analysis demonstrated the excellent bifunctional activity of SACs supported on MXene substrate across a broad pH range, especially in strongly alkaline media with record-low overpotentials. Further machine learning analysis shows that the d-band center, the charge of the active site, and the work function of the formed heterojunctions are critical to revealing the ORR/OER activity origin. Our results underscore the vast potential of strong interactions between different metal species in enhancing the durability and catalytic performance of SACs.

Cardiometabolic and Metabolic Profiles of Lean/Normal, Overweight and Obese Patients with Nonalcoholic Fatty Liver Disease.

Purpose: Disagreements about the risk of non-obese, non-alcoholic fatty liver disease for cardiometabolic outcomes occurred widely. This study aims to characterize the cardiometabolic and metabolic profile of lean/normal, overweight and obese patients with nonalcoholic fatty liver disease on a big sample. Patients and methods: Appeared healthy adults who participated in health examinations during the year of 2019-2022 were screened for fatty liver diagnosis. BMI classified fatty livers as lean, overweight and obese. Eleven cardiometabolic metrics (SBP: systolic blood pressure; DBP: diastolic blood pressure; TC: total cholesterol; TG: triglycerides; HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein cholesterol) and metabolic metrics (GLU: blood glucose; GHB: glycated haemoglobin; UA: uric acid; AST: aspartate aminotransferase; ALT: alanine aminotransferase) were included, described and compared among BMI categories. Results: There were 56,496 fatty livers diagnosed by ultrasound in this study. In total, the lean fatty liver had lowest mean SBP, DBP, GLU, TG, UA, AST, and ALT but highest TC and HDL among BMI categories (all p < 0.001). The number of abnormal metrics in total was 2.5, 2.9 and 3.4 in lean, overweight, and obesity, respectively (p < 0.001, p_trend < 0.001). Visualized data showed that lean fatty liver was similar but milder in all metabolic metrics than overweight and obesity at the young ages. However, lean fatty liver had higher coefficients of age and risk of metabolic abnormality regression (p <0.001 for SBP, DBP, GLU, GHB, TC). Conclusion: The lean type of fatty livers at a younger age has a relatively favourable cardiometabolic and metabolic profile compared to overweight and obese fatty livers. Due to the possible catch-up effect of metabolic dysfunctions in young lean fatty liver, lean fatty liver may have the same health outcomes as overweight/obesity fatty liver in long term. The evaluation and intervention may be critical for young lean fatty liver management to slowdown the rapid progress of metabolic dysfunction.

CircZNF609 inhibits miR-150-5p to promote high glucose-induced damage to retinal microvascular endothelial cells.

Hyperglycemia is a key contributor to diabetic macrovascular and ocular complications. It triggers a cascade of cellular damage, particularly in the retinal microvascular endothelial cells (RMECs). However, the underlying molecular mechanisms remain only partially understood. This study hypothesizes that CircZNF609 plays a pivotal role in mediating high glucose-induced damage in RMECs by modulating miR-150-5p and its downstream target genes, thereby affecting cellular survival, apoptosis, and oxidative stress. Gene expression datasets (GSE193974 and GSE160308) and clinical samples were used to investigate the expression levels of CircZNF609 and its interaction with miR-150-5p in the context of diabetic retinopathy (DR). Our results demonstrate that CircZNF609 is upregulated in both peripheral blood stem cells from DR patients and high glucose-stimulated hRMECs. Functional experiments reveal that silencing CircZNF609 improves cell viability, reduces apoptosis, inhibits tube formation, and modulates oxidative stress markers, whereas CircZNF609 overexpression exacerbates these effects. Moreover, miR-150-5p, a microRNA, was found to be negatively regulated by CircZNF609 and downregulated in DR. Its overexpression mitigates high glucose-induced cell injury. Our findings suggest a novel mechanism whereby CircZNF609 exacerbates high glucose-induced endothelial cell damage by sponging miR-150-5p, implicating the CircZNF609/miR-150-5p axis as a potential therapeutic target in diabetic retinopathy.

Degradation mechanisms and toxicity determination of bisphenol A by FeOx-activated peroxydisulfate under ultraviolet light.

Ultraviolet light (UV)-assisted advanced oxidation processes (AOPs) are commonly used to degrade organic contaminants. However, this reaction system's extensive comprehension of the degradation mechanisms and toxicity assessment remains inadequate. This study focuses on investigating the degradation mechanisms and pathways of bisphenol A (BPA), generation of reactive oxygen species (ROS), and toxicity of degradation intermediates in UV/PDS/ferrous composites (FeOx) systems. The degradation rate of BPA gradually increased from the initial 11.92% to 100% within 120 min. Sulfate radicals (SO4.-), hydroxyl radicals (.OH), superoxide anions (O2.-), and singlet oxygen (1O2) were the primary factors in the photocatalytic degradation of BPA in the UV/PDS/FeOx systems. The main reactions of BPA in this system were deduced to be ß-bond cleavage, hydroxyl substitution reaction, hydrogen bond cleavage, and oxidation reaction. A trend of decreasing toxicity for the degradation intermediates of BPA was observed according to the toxicity investigations. The efficient degradation of BPA in UV/PDS/FeOx systems provided theoretical data for AOPs, which will improve the understanding of organic contaminants by FeOx in natural industry wastewater.

Factors promoting and hindering resilience in youth with inflammatory bowel disease: A descriptive qualitative study.

AIM: To explore factors promoting and hindering resilience in youth with inflammatory bowel disease (IBD) based on Kumpfer's resilience framework. DESIGN: A descriptive qualitative study design with an interpretative approach was used. METHODS: Participants consisted of 10 youths with IBD from a tertiary hospital in Beijing (China) recruited using the purposive sampling method. Data were collected by semi-structured interviews from December 2020 to March 2021. The directed content analysis was performed for data analysis. RESULTS: Both promoting factors and hindering factors could be divided into personal factors and environmental factors. Thirteen themes were identified. The promoting factors included acceptance of illness, strict self-management, previous treatment experience, life goals, family support, medical support and peer encouragement. Stigma, lack of communication, negative cognition, societal incomprehension, economic pressure and academic and employment pressure were hindering factors. CONCLUSION: Health care professionals need to develop greater awareness of factors, stemming from both the individual and the outside world, that hinder or promote resilience in order to aid young patients with IBD. Building targeted nursing measures to excavate the internal positive quality of patients, provide external support and promote the development of resilience.

Recent advances in host-focused molecular tools for investigating host-gut microbiome interactions.

Microbial communities in the human gut play a significant role in regulating host gene expression, influencing a variety of biological processes. To understand the molecular mechanisms underlying host-microbe interactions, tools that can dissect signaling networks are required. In this review, we discuss recent advances in molecular tools used to study this interplay, with a focus on those that explore how the microbiome regulates host gene expression. These tools include CRISPR-based whole-body genetic tools for deciphering host-specific genes involved in the interaction process, Cre-loxP based tissue/cell-specific gene editing approaches, and in vitro models of host-derived organoids. Overall, the application of these molecular tools is revolutionizing our understanding of how host-microbiome interactions contribute to health and disease, paving the way for improved therapies and interventions that target microbial influences on the host.

Sexual dimorphism in thermogenic regulators and metrnl expression in adipose tissue of offspring mice exposed to maternal and postnatal overnutrition.

Current study investigated the impact of maternal and postnatal overnutrition on phenotype of adipose, in relation to offspring thermogenesis and sex. Female C57BL/6 J mice were fed with CHOW or high fat diet (HFD) for 2 weeks before mating, throughout gestation and lactation. At weaning, pups were fed to 9 weeks old with CHOW or HFD, which resulted in four groups for each gender--male or female: CHOW-CHOW (CC), CHOW-HFD (CH), HFD-CHOW (HC), HFD-HFD (HH). Maternal and post-weaning HFD enhanced thermogenic factors such as Acox1, Dio2 and Cox8b in iBAT of male and female offspring, but increased SIRT1, PGC-1α and UCP1 only in female. However, Acox1, Dio2 and Cox8b mRNA expression and SIRT1, PGC-1α and UCP1 protein expression were only enhanced upon maternal and post-weaning HFD in sWAT and pWAT of female offspring. Increased metrnl expression in adipose were observed in sex- and depot-specific manner, while enhanced circulating metrnl level was only observed in male offspring undergoing maternal HFD. Palmitic acid changed metrnl expression during preadipocytes differentiation and siRNA-mediated knockdown of metrnl inhibited preadipocyte differentiation. Female offspring were more prone to resist adverse outcomes induced by maternal and post-weaning overnutrition, which probably related to metrnl expression and thermogenesis.

OsKASI-2 is required for the regulation of unsaturation levels of membrane lipids and chilling tolerance in rice.

Chilling stress has seriously limited the global production and geographical distribution of rice. However, the molecular mechanisms associated with plant responses to chilling stress are less known. In this study, we revealed a member of ß-ketoacyl-ACP synthase I family (KASI), OsKASI-2 which confers chilling tolerance in rice. OsKASI-2 encodes a chloroplast-localized KASI enzyme mainly expressed in the leaves and anthers of rice and strongly induced by chilling stress. Disruption of OsKASI-2 led to decreased KAS enzymatic activity and the levels of unsaturated fatty acids, which impairs degree of unsaturation of membrane lipids, thus increased sensitivity to chilling stress in rice. However, the overexpression of OsKASI-2 significantly improved the chilling tolerance ability in rice. In addition, OsKASI-2 may regulate ROS metabolism in response to chilling stress. Natural variation of OsKASI-2 might result in difference in chilling tolerance between indica and japonica accessions, and Hap1 of OsKASI-2 confers chilling tolerance in rice. Taken together, we suggest OsKASI-2 is critical for regulating degree of unsaturation of membrane lipids and ROS accumulation for maintenance of membrane structural homeostasis under chilling stress, and provide a potential target gene for improving chilling tolerance of rice.

Effect of surface modification on the distribution of magnetic nanorings in hepatocellular carcinoma and immune cells.

Magnetic nanomaterial-mediated magnetic hyperthermia is a localized heating treatment modality that has been applied to treat aggressive cancer in clinics. In addition to being taken up by tumor cells to function in cancer therapy, magnetic nanomaterials can also be internalized by immune cells in the tumor microenvironment, which may contribute to regulating the anti-tumor immune effects. However, there exists little studies on the distribution of magnetic nanomaterials in different types of cells within tumor tissue. Herein, ferrimagnetic vortex-domain iron oxide nanorings (FVIOs) with or without the liver-cancer-targeting peptide SP94 have been successfully synthesized as a model system to investigate the effect of surface modification of FVIOs (with or without SP94) on the distribution of tumor cells and different immune cells in hepatocellular carcinoma (HCC) microenvironment of a mouse. The distribution ratio of FVIO-SP94s in tumor cells was 1.3 times more than that of FVIOs. Immune cells in the liver tumor microenvironment took up fewer FVIO-SP94s than FVIOs. In addition, myeloid cells were found to be much more amenable than lymphoid cells in terms of their ability to phagocytose nanoparticles. Specifically, the distributions of FVIOs/FVIO-SP94s in tumor-associated macrophages, dendritic cells, and myeloid-derived suppressor cells were 13.8%/12%, 3.7%/0.9%, and 6.3%/1.2%, respectively. While the distributions of FVIOs/FVIO-SP94s in T cells, B cells, and natural killer cells were 5.5%/0.7%, 3.0%/0.7%, and 0.4%/0.3%, respectively. The results described in this article enhance our understanding of the distribution of nanomaterials in the tumor microenvironment and provide a strategy for rational design of magnetic hyperthermia agents that can effectively regulate anti-tumor immune effects.

Intracellular Magnetic Hyperthermia Enables Concurrent Down-Regulation of CD47 and SIRPα To Potentiate Antitumor Immunity.

Harnessing the potential of tumor-associated macrophages (TAMs) to engulf tumor cells offers promising avenues for cancer therapy. Targeting phagocytosis checkpoints, particularly the CD47-signal regulatory protein α (SIRPα) axis, is crucial for modulating TAM activity. However, single checkpoint inhibition has shown a limited efficacy. In this study, we demonstrate that ferrimagnetic vortex-domain iron oxide (FVIO) nanoring-mediated magnetic hyperthermia effectively suppresses the expression of CD47 protein on Hepa1-6 tumor cells and SIRPα receptor on macrophages, which disrupts CD47-SIRPα interaction. FVIO-mediated magnetic hyperthermia also induces immunogenic cell death and polarizes TAMs toward M1 phenotype. These changes collectively bolster the phagocytic ability of macrophages to eliminate tumor cells. Furthermore, FVIO-mediated magnetic hyperthermia concurrently escalates cytotoxic T lymphocyte levels and diminishes regulatory T cell levels. Our findings reveal that magnetic hyperthermia offers a novel approach for dual down-regulation of CD47 and SIRPα, reshaping the tumor microenvironment to stimulate immune responses, culminating in significant antitumor activity.