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Cytokines are crucial regulators of inflammation and immune tolerance, making them promising targets for treating immune-related diseases like cancer, infections, and autoimmune disorders. While cytokine-based therapies have shown potential, challenges such as dose-limiting toxicity and suboptimal pharmacokinetics have constrained their clinical success. Recent advancements in nanotechnology offer innovative solutions to these limitations, particularly through the use of nanoparticle-based platforms that enhance cytokine delivery and neutralization. This review begins by examining the landscape of cytokine delivery, emphasizing how it can be accomplished using nanoparticle systems encapsulating proteins, DNA or mRNA payloads. We then discuss recent progress on platforms for nanoparticle-based cytokine neutralization, including nanoparticle–antibody complexes and cell membrane-coated nanoparticles. Finally, we highlight the latest clinical developments in cytokine-based therapies employing these strategies before addressing the critical challenges ahead that need to be overcome in order to fully realize the therapeutic potential of nanoparticle-based cytokine manipulation.

Inflammatory cytokines play a crucial role in the inflammatory response, and their aberrant expression and overproduction are closely associated with the development of many diseases. However, traditional inflammation treatment strategies are often accompanied by serious side effects, limiting their widespread use. In recent years, hydrogel, as a material with a three-dimensional network structure, good biocompatibility and modulability, has great potential for trapping and neutralizing inflammatory factors. Hydrogels can capture and neutralize inflammatory cytokines through various mechanisms such as electrostatic interactions, coupling with cytokine antibodies or binding nanoparticles. In addition, hydrogel microspheres, an important form of hydrogels, have excellent broad-spectrum binding of inflammatory cytokines in combination schemes with cell membranes. This article reviews recent research advances in hydrogel capture and neutralization of inflammatory cytokines, discussing the advantages of various mechanisms and their applications in different diseases. Overall, we believe that hydrogels are expected to further advance the development of therapeutic modalities for inflammatory diseases in the future.

The immense complexity and interconnectedness of inflammation and metabolism in the primary tumor ecosystem and pre-metastatic niches (PMN) present an enormous challenge for developing advanced nano-medicines for cancer immunotherapy. Herein, an intelligent tumor- and PMN-tropic bioactive “nano-med-fireman” (PsiL@M1M) was developed to not only arouse an appropriate photothermal immune cascade but also to “extinguish” the accompanying excessive inflammation. Ultimately, it aims to revitalize the immunosuppressive tumor microenvironment (TME) to spatiotemporally and effectively inhibit tumor metastasis and recurrence. PsiL@M1M was devised by incorporating the siRNA of lactate dehydrogenase A (siLDHA) on the functionalized photothermal mesoporous polydopamine (mPDA) and coupled with an M1-type macrophage membrane (M1M) to enable the capacity of inflammation targeting and modulation. PsiL@M1M actively accumulated and destroyed the primary tumor via photothermal therapy and subsequently mitigated the photothermal therapy-induced inflammatory cascade (e.g., epithelial mesenchymal transition) via cytokine neutralization, eliminating the supply of tumor-derived secretory factors as “nutrients” for PMN. Concurrently, siLDHA interfered with lactate (LA) production, inhibited inflammation-LA communication and relieved immune checkpoint, thus profoundly reversing the immunosuppressive microenvironment of both the primary tumor and PMN. Through cooperation, PsiL@M1M initiated normalized hypo-inflammatory photo-immunotherapy against both local tumor growth and spontaneous metastasis/recurrence. Our study provides a paradigm for a new generation of photothermal nano-medicines for the whole process of tumor treatment. Schematic representation of (A) the construction of “nano-med-fireman” (PsiL@M1M) and (B) the elicited spatiotemporal and hypo-inflammatory photo-immunotherapy against primary tumor and lung metastasis by inflammation neutralization and LA metabolic modulation. [Display omitted] •A biomimetic “nano-med-fireman” PsiL@M1M combining cytokine neutralization and lactate metabolic regulation was developed.•PsiL@M1M homes to tumor and neutralizes PTT-released inflammatory cytokines to alleviate treatment-induced inflammation.•PsiL@M1M blocks inflammation-lactate metabolic crosstalk for reprogramming the TME and reinvigorating cytotoxic T cells.•PsiL@M1M further regulates PMN to prevent tumor “seed” colonization and resist tumor metastasis/recurrence.

Non-small cell lung cancer (NSCLC) is known for rapid development and chronic inflammation-induced immunosuppression. IL-6 and IL-17A are the essential cytokines that facilitate NSCLC progression and myeloid-derived suppressive cell (MDSC)-mediated evasion. IL-6 or IL-17A targeting, especially IL-6, shown outstanding efficacy in patient NSCLC controlling, but failed to completely eradicate tumor. The local tumor multi-mode thermal therapy developed in our prior research was demonstrated to stimulate systemic and durable tumor-specific immune response thereby promoting long-term tumor-free survival of mice and prolong the progression-free survival of patients, although the therapeutic efficacy was still affected by high-level preoperative MDSCs. To further improve the efficacy, in this study, IL-6 and IL-17A neutralization were combined with multi-mode thermal therapy in mouse LLC1 NSCLC model. Study revealed that combined with single cytokine neutralization only prolonged the survival time while triple combination therapy efficiently improved the survival rate. Additionally, triple combination therapy reduced the accumulation of MDSCs but promoted their maturation with strengthened activation and function of myeloid cells, thereby triggering a Th1-dominant-CD4 +  T cell-response and enhancing the malignant cell-killing capacity of immune cells. Our study highlights the extraordinary efficacy of combining multi-mode thermal therapy with IL-6 and IL-17A neutralization, revealing a new strategy for refractory NSCLC patients. Graphical Abstract Highlights • Combining multi-mode thermal therapy with anti-IL-6&IL-17A promotes survival of NSCLC mice • Triple combination therapy reduces the proportion of MDSCs and arouses CD4 +  Th1 immunity • Triple combination therapy enhances T and NK cell-mediated tumor-killing

The management of chronic inflammatory diseases, such as inflammatory bowel disease, psoriasis, and rheumatoid arthritis has significantly improved over the last decade with the clinical availability of anti-TNF-α biologics. Despite this undoubted treatment success, a combination of acquired resistance together with an increased risk of systemic complications, means that a significant number of patients either fail to find a suitable targeted therapy or frustratingly discover that an approach that did work is no longer efficacious. Here, we report the isolation and characterization of a new class of super-neutralizing anti-TNF-α biologics formats, the building blocks of which were originally derived as variable new antigen receptor (VNAR) domains from an immunized nurse shark. These parental small, stable VNAR monomers recognize and neutralize tumor necrosis factor (TNF)-α, in cell-based assays, at nanomolar concentrations. However, the simple, single-chain molecular architecture of VNARs allows for easy and multiple reformatting options. Through reformatting, we achieved a 50,000-fold enhancement in efficacy with super-neutralizing fusion proteins able to block TNF-α induced cytotoxicity in the 2-5 pM range while retaining other functionality through the addition of fusion proteins known to extend serum half-life . In an intestinal epithelial barrier dysfunction efficacy model, the lead VNAR domains, restored barrier function and prevented paracellular flux with comparable efficacy to adalimumab (Humira ). In addition, all multivalent VNAR constructs restored trans-epithelial electrical resistance (TEER) to approximately 94% of the untreated control. Reformatted VNAR domains should be considered as a new class of biologic agents for the treatment of hTNF-α driven diseases; either used systemically with appropriate half-life extension or alternatively where site-specific delivery of small and stable neutralizers may provide improvements to current therapy options.

[...]obesity poses an elevated risk of severe infection with COVID-19, which may contribute to the need for mechanical ventilation in intensive care units and in the high incidence of mortality with premature death (5). [...]the understanding of adipose tissue as an inert storage depot started to shift. The specificity of IL-6 in COVID-19 among cytokines comes from the fact that increased IL-6 is associated with the intensity of the inflammatory cytokine storms. [...]targeting tocilizumab and siltuximab monoclonal antibodies to IL-6 and its receptor (IL-6R) could alleviate cytokine-related symptoms in serious COVID-19 patients (11) and in obese patients with COVID-19 who may have elevated levels of inflammatory markers such as IL-6. Analysis of T cells in obese mice has led researchers to recognize that most of them are ‘depleted’, a concept of immunology that suggests slow proliferation and that they do not produce chemical messengers for contact with other immune cells (12). [...]in obesity, T cells are thought to release higher levels of programmed cell death-1 (PD-1) protein, which prevents the killing of tumor cells by cytotoxic T cells, thereby facilitating the development and growth of tumors (13).

Previous work has indicated that both Borrelia burgdorferi and the process of tick feeding (saliva) modulate the host immune response. Molecules have been identified in tick saliva that effect T cell proliferation by binding to specific cytokines, thereby promoting a Th2 cytokine response that does not afford protection against tick-transmitted B. burgdorferi in mice. Moreover, reconstitution of a Th1-biased T cell response prior to spirochete challenge effectively neutralizes tick modulation of host immunity and affords protection against tick transmission of spirochetes. The current studies were undertaken to determine the effect of neutralizing specific Th2 cytokines prior to tick feeding and subsequent transmission of B. burgdorferi. The results indicate that suppression of both IL-4 and IL-5 prior to the feeding of B. burgdorferi-infected ticks significantly decreased spirochete load in target organs such as joint, bladder, heart, and skin of the Lyme disease-susceptible host.

Objectives: AAV vectors are widely used in gene therapy, but the prevalence of neutralizing antibodies raised against AAV serotypes in the course of a natural infection, as well as innate and adaptive immune responses induced upon vector administration, is still considered an important limitation. In ocular gene therapy, vectors applied subretinally bear the risk of retinal detachment or vascular leakage. Therefore, new AAV vectors that are suitable for intravitreal administration for photoreceptor transduction were developed. Methods: Here, we compared human immune responses from donors with suspected previous AAV2 infections to the new vectors AAV2.GL and AAV2.NN—two capsid peptide display variants with an enhanced tropism for photoreceptors—with the parental serotype AAV2 (AAV2 WT). We investigated total and neutralizing antibodies, adaptive and innate cellular immunogenicity determined by immunofluorescence staining and flow cytometry, and cytokine secretion analyzed with multiplex beads. Results: While we did not observe obvious differences in overall antibody binding, variants—particularly AAV2.GL—were less sensitive to neutralizing antibodies than the AAV2 WT. The novel variants did not differ from AAV2 WT in cellular immune responses and cytokine production in vitro. Conclusion: Due to their enhanced retinal tropism, which allows for dose reduction, the new vector variants are likely to be less immunogenic for gene therapy than the parental AAV2 vector.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has highlighted the urgent need to rapidly develop therapeutic strategies for such emerging viruses without effective vaccines or drugs. Here, we report a decoy nanoparticle against COVID-19 through a powerful two-step neutralization approach: virus neutralization in the first step followed by cytokine neutralization in the second step. The nanodecoy, made by fusing cellular membrane nanovesicles derived from human monocytes and genetically engineered cells stably expressing angiotensin converting enzyme II (ACE2) receptors, possesses an antigenic exterior the same as source cells. By competing with host cells for virus binding, these nanodecoys effectively protect host cells from the infection of pseudoviruses and authentic SARS-CoV-2. Moreover, relying on abundant cytokine receptors on the surface, the nanodecoys efficiently bind and neutralize inflammatory cytokines including interleukin 6 (IL-6) and granulocyte–macrophage colony-stimulating factor (GM-CSF), and significantly suppress immune disorder and lung injury in an acute pneumonia mouse model. Our work presents a simple, safe, and robust antiviral nanotechnology for ongoing COVID-19 and future potential epidemics.