Immunomodulatory Approaches Research Articles

Chimeric Peptide Functionalized Immunostimulant to Orchestrate Photodynamic Immunotherapeutic Effect by PD-L1 Deglycosylation and CD47 Inhibition.

Breast cancer utilizes diverse immunosuppressive mechanisms to evade immune surveillance, thereby impairing immunotherapeutic effects. In this work, a chimeric peptide functionalized immunostimulant (designated as aGlyR) is fabricated to boost photodynamic immunotherapy through PD-L1 deglycosylation and CD47 inhibition. The photosensitizer protoporphyrin IX (PpIX) is conjugated to a PD-L1 deglycosylation peptide via a hydrophilic PEG8 linker, yielding the chimeric peptide Fmoc-K(PpIX)-PEG8-GFTATPPAPDSPQEP. This chimeric peptide could self-assemble into nanomicelles capable of encapsulating the CD47 inhibitor RRx-001, generating the multifunctional photodynamic immunostimulant aGlyR. In vitro and in vivo results indicate that the photodynamic therapy (PDT) of aGlyR could disrupt breast cancer cells and trigger immunogenic cell death (ICD), leading to the release of tumor-associated antigens (TAAs) and the activation of immunological cascades. Additionally, the chimeric peptide component of aGlyR results in the deglycosylation and degradation of PD-L1, which restores T cell-mediated immune activity. Concurrently, the release of RRx-001 blocks the CD47 pathway, disrupting the antiphagocytic signaling of breast cancer cells and activating innate immune responses. This synergistic immunomodulatory approach effectively reverses the complex immunosuppressive factors, significantly enhancing the immunotherapeutic effects of conventional treatments.

Masterful macrophages: understanding and targeting activation dysfunction in diabetic wounds

Abstract Diabetes mellitus is a group of chronic metabolic diseases worldwide seriously threatens human health and increases social and economic burden; underlying drivers of impaired healing include uncontrolled inflammation, repeated ischemia–reperfusion injury, and neuropathy alongside infection risks. Macrophages orchestrate standard repair, exhibit sustained classical pro-inflammatory activation in diabetes, disrupting growth factor secretion, angiogenesis, and matrix regulation. Hyperglycemia- mediated advanced glycation end products and reactive oxygen species heighten pattern recognition receptor stimulation, causing reduced alternative macrophage differentiation. Promising immunomodulation approaches redirecting their phenotypes to resolve inflammation and stimulate regeneration provides optimism. We discuss macrophage origination, polarization dynamics, diabetic wound phenotypic imbalance, and critical microenvironmental disruptions perpetuating pathological function. Elucidating specific regulatory nodes upholding their activation states will inform intelligent targeting opportunities. Overall, infiltrating macrophages constitute indispensable yet amenable diabetic wound healing coordinators.

Structure-Based Design of Novel TLR7/8 Agonist Payloads Enabling an Immunomodulatory Conjugate Approach.

Dual activation of the TLR7 and TLR8 pathways leads to the production of type I interferon and proinflammatory cytokines, resulting in efficient antigen presentation by dendritic cells to promote T-cell priming and antitumor immunity. We developed a novel series of TLR7/8 dual agonists with varying ratios of TLR7 and TLR8 activity for use as payloads for an antibody-drug conjugate approach. The agonist-induced production of several cytokines in human whole blood confirmed their functional activity. Structure-activity relationship studies guided by structure-based drug design are described.

The effect of transcutaneous auricular vagus nerve stimulation on cardiovascular function in subarachnoid hemorrhage patients: A randomized trial.

Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. However, the effects of taVNS on cardiovascular dynamics in critically ill patients, like those with SAH, have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population. Therefore, this study assessed the impact of both acute and repetitive taVNS on cardiovascular function. In this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram readings and vital signs. We compared long-term changes in heart rate, heart rate variability (HRV), QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored acute cardiovascular biomarkers in patients exhibiting clinical improvement. We found that repetitive taVNS did not significantly alter heart rate, QT interval, blood pressure, or intracranial pressure (ICP). However, repetitive taVNS increased overall HRV and parasympathetic activity compared to the sham treatment. The increase in parasympathetic activity was most pronounced from 2 to 4 days after initial treatment (Cohen's d = 0.50). Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, ICP, or HRV. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than one point in their modified Rankin Score at the time of discharge. Our study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment. The American Association of Neurological Surgeons (ALH), The Aneurysm and AVM Foundation (ALH), The National Institutes of Health R01-EB026439, P41-EB018783, U24-NS109103, R21-NS128307 (ECL, PB), McDonnell Center for Systems Neuroscience (ECL, PB), and Fondazione Neurone (PB). NCT04557618.

Phase I trial of phIL12 plasmid intratumoral gene electrotransfer in patients with basal cell carcinoma in head and neck region.

In the treatment of cancer, immunomodulatory approaches are developed to support the organism in fighting cancer or to enhance the immunomodulatory effects of local ablative techniques. To this end, we conducted an interventional, open-label, single-arm Phase I trial to evaluate the safety and tolerability of intratumoral phIL12 plasmid DNA gene electrotransfer as primary objectives. The study was dose-escalating with 3 consecutive cohorts of 3 patients per phIL12 dose level (0.5mg/ml, 1mg/ml or 2mg/ml) according to a matched 3+3 design. Recruitment of patients was staggered. The waiting period was 30 days after treatment of the previous patient, based on the expected duration of acute and subacute toxicity. The results of this phase I clinical trial in basal cell carcinoma demonstrated the feasibility and safety of the phIL12 plasmid by gene electrotransfer. We were able to demonstrate that phIL12 gene electrotransfer induced local IL-12 production, which was accompanied with IFN-γ expression. Triggering of the immune response was demonstrated by increased infiltration of immune cells and some antitumor effect. Based on these data, we would recommend the use of a concentration of 2mg/ml of the plasmid in future trials. The trial lays the foundation for future Phase II clinical trials in which phIL12 gene electrotransfer is used in combination with local tumor-ablative approaches, such as electrochemotherapy or radiotherapy.

Advancing Aquaculture Integrating Microbiome Modulation, Immunomodulatory Approaches, and Mitigating Environmental Stressors in Nile Tilapia Farming

Sustainable aquaculture methods must be advanced to meet the problems presented by environmental stresses and the expanding worldwide need for food. This study examines cutting-edge methods for raising Nile tilapia (Oreochromis niloticus), emphasizing immunomodulatory techniques, microbiome modification, and the crucial task of reducing environmental stresses to increase resilience and production. Probiotics, prebiotics, and synbiotics are important in enhancing nutrition absorption, promoting disease resistance, and optimizing gut health, making microbiome modification an essential strategy. The use of functional feeds enhanced with bioactive chemicals and the creation of tailored vaccinations are two examples of advances in immunomodulatory approaches that have demonstrated promise in bolstering tilapia's immune systems against pathogenic threats. A holistic strategy to guarantee sustainable production is provided by simultaneously reducing environmental stresses, such as hypoxia, variable water temperatures, and pollutant exposure, through enhanced aquaculture systems, water quality control, and stress-resilient fish strains. The importance of addressing these environmental stressors is underscored, as they pose significant threats to the industry. Emerging technologies like genomics, transcriptomics, and precision aquaculture tools, which allow for the monitoring and adjusting of farming operations to suit the unique requirements of Nile tilapia, further facilitate the integration of these tactics. This review highlights the potential of comprehensive, science-driven methods in converting Nile tilapia farming into a resilient, sustainable, and fruitful enterprise and emphasizes the importance of addressing environmental stressors in this transformation.

Iron Oxide Nanoparticles Induce Macrophage Secretion of ATP and HMGB1 to Enhance Irradiation-Led Immunogenic Cell Death.

ATP (adenosine triphosphate) and HMGB1 (high mobility group box 1 protein) are key players in treatments that induce immunogenic cell death (ICD). However, conventional therapies, including radiotherapy, are often insufficient to induce ICD. In this study, we explore a strategy using nanoparticle-loaded macrophages as a source of ATP and HMGB1 to complement radiation-induced intrinsic and adaptive immune responses. To this end, we tested three inorganic particles, namely, iron oxide nanoparticles (ION), aluminum oxide nanoparticles (AON), and zinc oxide nanoparticles (ZON), in vitro with bone marrow-derived dendritic cells (BMDCs) and then in vivo in syngeneic tumor models. Our results showed that ION was the most effective of the three nanoparticles in promoting the secretion of ATP and HMGB1 from macrophages without negatively affecting macrophage survival. Secretions from ION-loaded macrophages can activate BMDCs. Intratumoral injection of ION-loaded macrophages significantly enhanced tumor infiltration and activation of dendritic cells and cytotoxic T cells. Moreover, exogenous ION macrophages can enhance the efficacy of radiotherapy. In addition, direct injection of ION can also enhance the efficacy of radiotherapy, which is attributed to ION uptake by and stimulation of endogenous macrophages. Instead of directly targeting cancer cells, our strategy targets macrophages and uses them as a secretory source of ATP and HMGB1 to enhance radiation-induced ICD. Our research introduces a new nanoparticle-based immunomodulatory approach that may have applications in radiotherapy and beyond.

Crystal structure of the human LAG-3-HLA-DR1-peptide complex.

T cell activity is governed by T cell receptor (TCR) signaling and constrained by immune checkpoint molecules, including programmed cell death protein 1 (PD-1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and lymphocyte activation gene 3 (LAG-3). The basis for how LAG-3 binds to human leukocyte antigen class II molecules (HLA-II) remains unknown. Here, we present the 3.4-angstrom crystal structure of a LAG-3-peptide-HLA-II complex and probe the energetics of the complex interface. Coincident with the HLA-II binding site of the ancestrally related, monomeric CD4 receptor, the LAG-3 homodimer laterally engages two HLA-II molecules via distal D1 domain surfaces, imposing a 38° angular offset. The LAG-3-HLA-II interface is discontinuous and lacks involvement of the D1 extra loop, a binding site for anti-LAG-3 therapeutic monoclonal antibodies. Upon HLA-II binding, intrinsically mobile loops of the LAG-3 molecule become ordered, with contact residues highly conserved across HLA-DR, DQ, and DP allomorphs. Our data provide a structural foundation for development of immunomodulatory approaches targeting LAG-3.

Relapse-free survival is progressively shortened in a subset of Black patients with immune-mediated TTP treated in the rituximab era.

Immune thrombotic thrombocytopenic purpura (iTTP) is a chronically relapsing disorder caused by autoantibody-mediated deficiency of ADAMTS13. Rituximab is frequently administered to prevent relapses, but whether the durability of rituximab effect is maintained with subsequent treatment courses has not been studied. Using the United States Thrombotic Microangiopathy Consortium (USTMA) retrospective iTTP registry, we evaluated clinical relapse-free survival (RFS) with subsequent courses of rituximab treatment in multiply relapsing patients. Separately, we evaluated overall RFS (composite of time to clinical relapse, ADAMTS13 relapse, or preemptive rituximab) in a prospective iTTP cohort from the Johns Hopkins University and the University of Minnesota. In the USTMA registry, median clinical RFS was shorter after the second or subsequent rituximab-treated episode than the first (2.1 vs 6.0 years; P=.04). White patients' clinical relapse risk after the second and subsequent rituximab courses was not significantly different compared with the first (hazard ratio [HR], 1.86; 95% confidence interval [CI], 0.22-15.80; P=.57), whereas for Black patients, clinical relapse risk was significantly higher after the second or subsequent courses (HR, 2.82; 95%CI, 1.52-5.24; P=.001). In the prospective cohort, overall RFS progressively shortened after each episode of rituximab treatment with the first episode having the longest RFS (2.8 years; interquartile range, 2.0-6.0) and this loss of response durability was most pronounced in Black patients. The durability of rituximab's effect declines with subsequent treatments, which is more pronounced in Black patients, who may benefit from closer monitoring and alternative immunomodulatory approaches such as maintenance rituximab and consideration of other agents.

Therapeutic evaluation of low‐dose IL‐2‐based immunomodulatory approach in patients with early AD

Therapeutic evaluation of low‐dose IL‐2‐based immunomodulatory approach in patients with early AD

Immune therapeutic strategies for the senescent tumor microenvironment.

Senescent cells can either to promote immunosuppressive tumor microenvironment or facilitate immune surveillance. Despite the revolutionary impact of cancer immunotherapy, durable responses in solid tumors, particularly in advanced stages, remain limited. Recent studies have shed light on the influence of senescent status within the tumor microenvironment (TME) on therapy resistance and major efforts are needed to overcome these challenges. This review summarizes recent advancements in targeting cellular senescence, with a particular focus on immunomodulatory approaches on the hallmarks of cellular senescence.

A coumarin derivative C7 exhibits antiviral activity against WSSV by reducing phosphatidylcholine content in shrimp

The white spot syndrome virus (WSSV) causes white spot disease (WSD), a severe condition in crustacean aquaculture, leading to significant economic losses. Our previous study demonstrated that C7 is an effective therapeutic agent against WSSV infection in aquaculture. It specifically blocked viral horizontal transmission and reduced shrimp mortality in a dose- and time-dependent manner. Here, we report the potential antiviral mechanism of C7 in shrimp. C7 regulated abnormal glycerophospholipid metabolism caused by WSSV and inhibited phosphatidylcholine (PC) synthesis by more than twofold, potentially enhancing shrimp resistance to viral infection. As the primary phospholipid in the cell membrane, PC is one of the main reactants in lipid peroxidation. Our results indicated that C7 significantly reduced the levels of lipid peroxidation products 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) induced by WSSV, whereas PC had the opposite effect. Accumulation of lipid peroxidation products inhibits stimulator of interferon genes (STING) signaling. Further evidence showed that C7 promoted STING transport from the endoplasmic reticulum to the Golgi apparatus, significantly activating the expression of the shrimp interferon analogue Vago4 gene. In contrast, PC suppressed Vago4 expression. Our results demonstrated that C7 inhibited PC synthesis, reduced the degree of lipid peroxidation, promoted STING translocation, activated Vago4 expression, and ultimately exerted antiviral effects. Therefore, C7 exhibits immunoregulatory activity as a preventative agent for enhancing the innate immunity of shrimp, making it potentially useful for future immunomodulatory approaches.

Development and Evaluation of Indole-Based Phospholipase D Inhibitors for Lung Cancer Immunotherapy.

This study explored novel immunomodulatory approaches for cancer treatment, with a specific focus on lung cancer, the leading cause of cancer-related deaths worldwide. We synthesized indole-based phospholipase D (PLD) inhibitors with various substituents to improve anticancer efficacy. Through structure-activity relationship studies, the key compound was identified that significantly inhibiting PLD, suppressing cell growth, viability, and migration in vitro, while inducing apoptosis of lung cancer cells. In silico docking studies confirmed its binding to the PLD1 active site, highlighting the role of specific residues in inhibiting PLD1 activity. The inhibitor modulated oncogenic pathways and immune evasion in lung cancer cells, showing potential for immunotherapy. In vivo experiments in a mouse model showed tumor reduction and immune response alteration. Combining these inhibitors with gemcitabine, an anticancer drug, synergistically enhanced inhibition of lung cancer cell apoptosis and proliferation. This research offers new insights into PLD inhibitor as potential cancer therapeutics.

The impact of omega-3 fatty acids in a combined experimental model of periodontitis and metabolic syndrome

Relevance. Periodontitis and metabolic syndrome are interrelated conditions that often aggravate each other through shared pathogenic mechanisms, highlighting the need for integrated immunomodulatory therapeutic approaches. Despite this, existing literature presents inconsistent data regarding the interplay between periodontitis and metabolic syndrome, as well as limited insights into the potential benefits of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) as an adjuvant therapy. Specifically, the role of ω-3 PUFAs in modulating the inflammatory response and mitigating bone resorption remains inadequately explored. Therefore, this study aims to evaluate the inflammatory response and osteoresorption in periodontal tissues under the combined conditions of periodontitis and metabolic syndrome, while also assessing the therapeutic effects of ω-3 PUFAs.Materials and methods. This experimental study was conducted using 30 male Wistar rats, which were randomly assigned to one of five groups: a control group, a periodontitis group, a combined periodontitis and metabolic syndrome group, a periodontitis group treated with omega-3 fatty acids, and a combined periodontitis and metabolic syndrome group treated with omega-3 fatty acids. The study employed several research methodologies. Biochemical analyses were performed to confirm the presence of metabolic syndrome. Histopathological and morphometric assessments were conducted to evaluate the inflammatory response, the extent of osteoresorption, and the number of osteoclasts in the periodontal tissues. Additionally, molecular genetic analysis was used to measure the relative mRNA expression levels of key inflammatory and osteoclastogenic markers, including TNFα, IL-1β, RANK, and OPG.Results. The data demonstrated that metabolic syndrome in laboratory animals significantly exacerbates both the pro-inflammatory response and the extent of lacunar osteoclastic bone resorption. Administration of ω-3 PUFAs at a dose of 40 mg/kg over 30 days led to a statistically significant reduction in inflammatory infiltration within the periodontal tissues (3.17 ± 0.21 in the control group vs. 1.83 ± 0.21 in the treated group, р = 0.001) and a decrease in the number of osteoclasts (3,75 ± 0,45 in the control group vs. 1,75 ± 0,35 in the treated group, р = 0.003). Additionally, there was a notable reduction in the expression levels of TNFα, IL-1β, and RANK mRNA. Similar but less pronounced effects were observed in the group with combined metabolic syndrome following ω-3 PUFA administration.Conclusion. These findings enhance the current understanding of the interplay between periodontitis and metabolic syndrome, highlighting the potential of ω-3 PUFAs as a preventive or therapeutic intervention. ω-3 PUFAs may be effective in mitigating inflammatory responses and bone resorption, both in cases of isolated periodontitis and when accompanied by metabolic syndrome.

The effect of transcutaneous auricular vagus nerve stimulation on cardiovascular function in subarachnoid hemorrhage patients: a safety study.

Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. However, the effects of taVNS on cardiovascular dynamics in critically ill patients, like those with SAH, have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population. Therefore, we assessed the impact of both acute taVNS and repetitive taVNS on cardiovascular function in this study. In this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a Sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram (ECG) readings and vital signs. We compared long-term changes in heart rate, heart rate variability, QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored acute cardiovascular biomarkers in patients exhibiting clinical improvement. We found that repetitive taVNS did not significantly alter heart rate, QT interval, blood pressure, or intracranial pressure. However, taVNS increased overall heart rate variability and parasympathetic activity compared to the sham treatment. The increase in parasympathetic activity was most pronounced from 2-4 days after initial treatment (Cohen's d = 0.50). Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, intracranial pressure, or heart rate variability. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than one point in their Modified Rankin Score at the time of discharge. Our study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment. NCT04557618.

Recurrent adamantinomatous craniopharyngiomas show MAPK pathway activation, clonal evolution and rare TP53-loss-mediated malignant progression

The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP). We show the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP, and analysis of additional whole genome sequencing data from the Children’s Brain Tumour Network confirms chromosomal arm copy number changes in at least 7/67 ACP cases. The activation of the MAPK/ERK pathway, a feature previously shown in primary ACP, is observed in all but one recurrent cases of ACP. The only ACP without MAPK activation is an aggressive case of recurrent malignant human craniopharyngioma harbouring a CTNNB1 mutation and loss of TP53. Providing support for a functional role of this TP53 mutation, we show that Trp53 loss in a murine model of ACP results in aggressive tumours and reduced mouse survival. Finally, we characterise the tumour immune infiltrate showing differences in the cellular composition and spatial distribution between ACP and PCP. Together, these analyses have revealed novel insights into recurrent craniopharyngioma and provided preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in against recurrent ACP.

Exploratory phase I study of HF1K16 for the treatment of patients with refractory/recurrent advanced glioma.

TPS32 Background: Glioblastoma (GBM) is the most common primary and aggressive malignant brain tumor in adults. Almost all patients with glioblastoma eventually have disease relapse and the median overall survival (OS) remains at only 30 weeks for those recurrent GBM patients. However, very few therapies had been approved over the past two decades, emphasizing the need for novel treatments. It is now wildly acknowledged that the immune microenvironment in brain offers adequate opportunities to implement immunotherapy for the treatment. Since most recurrent tumors had previously been exposed to the genotoxic stress of irradiation and/or chemotherapy, it is predicted to resulted in a higher mutational load and more immunogenic. However, The limited success of T cell immunomodulatory approach for advanced glioma has prompted a deeper understanding of the brain tumor and the immune microenvironment. GBM tumors are well-appreciated to be a immunosuppressive and a hallmark of GBM immunosuppression is the appearance of circulating myeloid-derived suppressor cells (MDSCs) at higher levels. Our preliminary data suggests that HF1K16, a liposome ATRA (all trans retinoic acid) suspension, is capable of relieving immune suppression induced by MDSCs. Further, we recently completed a phase I dose escalation study which showed that HF1K16 is safe, well-tolerated with preliminary efficacy in brain tumor. Thus, we hypothesized that HF1K16 may reverse GBM-associated immune suppression and leading to an increase in TILs and improved survival. Methods: This is an advanced glioma-specific expansion arm for adult patients with prior confirmed brain tumor and failed standard treatment. We plan to enroll 20~30 evaluable patients. Key eligibility criteria include candidates age ≥ 18 years, Karnofsky performance status ≥ 60 with and at least one measurable lesion. The primary endpoint is determination of overall response rate (ORR), duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) according to RANO criteria. Secondary endpoints include longitudinal assessment of the peripheral immune response by changes in MDSC and T cell subsets and numbers. HF1K16 infusions were administered in 21-day cycles (q.o.d days 1-14). Prior to and during treatment, peripheral blood mononuclear cells were collected and analyzed with flow cytometry to monitor the changes in myeloid cell phenotype and T cell composition. The recruitment of patients is anticipated completed in 2024. Clinical trial information: NCT05388487 .

Unveiling the governing role of ‘remodeling triangle area’ in soft-hard tissue interface equilibrium for metal implants advancement

Metal implants holds significant promise for diverse fixed prostheses. However, their long-term reliability and broader application are hindered by challenges related to the disequilibrium at the soft-hard tissue interface. By using anti-inflammatory (PDA/IL4) and pro-inflammatory (PDA/LPS/IFNγ) coatings to modulate distinct immune characteristics, we discovered a dynamic bioactive structure at the soft-hard tissue interface around metal implant, which we have named the 'Remodeling Triangle Area' (RTA). We further demonstrate that the RTA can be influenced by the PDA/IL4 coating to favor a phenotype that enhances both innate and adaptive immunity. This leads to stronger epithelial adhesion, the formation of dense connective tissue via IGF1 secretion, and a more balanced soft-hard tissue interface through the OPG/RANKL axis. Conversely, the PDA/LPS/IFNγ coating shifts the RTA towards a phenotype that activates the innate immune response. This results in a less cohesive tissue structure and bone resorption, characterized by reduced IGF1 secretion and an imbalanced OPG/RANKL axis. Over all, our study introduces the novel concept termed the 'Remodeling Triangle Area' (RTA), an immune-rich anatomical region located at the nexus of the implant interface, epithelial, connective, and bone tissue, which becomes highly interactive post-implantation to modulate the soft-hard tissue interface equilibrium. We believe that an RTA-centric, immunomodulatory approach has the potential to revolutionize the design of next-generation metal implants, providing unparalleled soft-hard tissue interface equilibrium properties.

Advances and Challenges in Immune-Modulatory Biomaterials for Wound Healing Applications.

Wound healing progresses through three distinct stages: inflammation, proliferation, and remodeling. Immune regulation is a central component throughout, crucial for orchestrating inflammatory responses, facilitating tissue repair, and restraining scar tissue formation. Elements such as mitochondria, reactive oxygen species (ROS), macrophages, autophagy, ferroptosis, and cytokines collaboratively shape immune regulation in this healing process. Skin wound dressings, recognized for their ability to augment biomaterials' immunomodulatory characteristics via antimicrobial, antioxidative, pro- or anti-inflammatory, and tissue-regenerative capacities, have garnered heightened attention. Notwithstanding, a lack of comprehensive research addressing how these dressings attain immunomodulatory properties and the mechanisms thereof persists. Hence, this paper pioneers a systematic review of biomaterials, emphasizing immune regulation and their underlying immunological mechanisms. It begins by highlighting the importance of immune regulation in wound healing and the peculiarities and obstacles faced in skin injury recovery. This segment explores the impact of wound metabolism, infections, systemic illnesses, and local immobilization on the immune response during healing. Subsequently, the review examines a spectrum of biomaterials utilized in skin wound therapy, including hydrogels, aerogels, electrospun nanofiber membranes, collagen scaffolds, microneedles, sponges, and 3D-printed constructs. It elaborates on the immunomodulatory approaches employed by these materials, focusing on mitochondrial and ROS modulation, autophagic processes, ferroptosis, macrophage modulation, and the influence of cytokines on wound healing. Acknowledging the challenge of antibiotic resistance, the paper also summarizes promising plant-based alternatives for biomaterial integration, including curcumin. In its concluding sections, the review charts recent advancements and prospects in biomaterials that accelerate skin wound healing via immune modulation. This includes exploring mitochondrial transplantation materials, biomaterial morphology optimization, metal ion incorporation, electrostimulation-enabled immune response control, and the benefits of composite materials in immune-regulatory wound dressings. The ultimate objective is to establish a theoretical foundation and guide future investigations in the realm of skin wound healing and related materials science disciplines.

Nanotechnology-Mediated Immunomodulation Strategy for Inflammation Resolution.

Inflammation serves as a common characteristic across a wide range of diseases and plays a vital role in maintaining homeostasis. Inflammation can lead to tissue damage and the onset of inflammatory diseases. Although significant progress is made in anti-inflammation in recent years, the current clinical approaches mainly rely on the systemic administration of corticosteroids and antibiotics, which only provide short-term relief. Recently, immunomodulatory approaches have emerged as promising strategies for facilitating the resolution of inflammation. Especially, the advanced nanosystems with unique biocompatibility and multifunctionality have provided an ideal platform for immunomodulation. In this review, the pathophysiology of inflammation and current therapeutic strategies are summarized. It is mainly focused on the nanomedicines that modulate the inflammatory signaling pathways, inflammatory cells, oxidative stress, and inflammation targeting. Finally, the challenges and opportunities of nanomaterials in addressing inflammation are also discussed. The nanotechnology-mediated immunomodulation will open a new treatment strategy for inflammation therapy.