Immunostimulatory Activity Research Articles

Modularized viromimetic polymer nanoparticle vaccines (VPNVaxs) to elicit durable and effective humoral immune responses.

Virus-like particle (VLP) vaccines had shown great potential during the COVID-19 pandemic, and was thought to be the next generation of antiviral vaccine technology due to viromimetic structures. However, the time-consuming and complicated processes in establishing a current recombinant-protein-based VLP vaccine has limited its quick launch to the out-bursting pandemic. To simplify and optimize VLP vaccine design, we herein report a kind of viromimetic polymer nanoparticle vaccine (VPNVax), with subunit receptor-binding domain (RBD) proteins conjugated to the surface of polyethylene glycol-b-polylactic acid (PEG-b-PLA) nanoparticles for vaccination against SARS-CoV-2. The preparation of VPNVax based on synthetic polymer particle and chemical post-conjugation makes it possible to rapidly replace the antigens and construct matched vaccines at the emergence of different viruses. Using this modular preparation system, we identified that VPNVax with surface protein coverage of 20%-25% had the best immunostimulatory activity, which could keep high levels of specific antibody titers over 5 months and induce virus neutralizing activity when combined with an aluminum adjuvant. Moreover, the polymer nano-vectors could be armed with more immune-adjuvant functions by loading immunostimulant agents or chemical chirality design. This VPNVax platform provides a novel kind of rapidly producing and efficient vaccine against different variants of SARS-CoV-2 as well as other viral pandemics.

Co-Formulation of Recombinant Porcine IL-18 Enhances the Onset of Immune Response in a New Lawsonia intracellularis Vaccine.

Pig is one of the most consumed meats worldwide. One of the main conditions for pig production is Porcine Enteropathy caused by Lawsonia intracellularis. Among the effects of this disease is chronic mild diarrhea, which affects the weight gain of pigs, generating economic losses. Vaccines available to prevent this condition do not have the desired effect, but this limitation can be overcome using adjuvants. Pro-inflammatory cytokines, such as interleukin 18 (IL-18), can improve an immune response, reducing the immune window of protection. In this study, recombinant porcine IL-18 was produced and expressed in Escherichia coli and Pichia pastoris. The protein's biological activity was assessed in vitro and in vivo, and we determined that the P. pastoris protein had better immunostimulatory activity. A vaccine candidate against L. intracellularis, formulated with and without IL-18, was used to determine the pigs' cellular and humoral immune responses. Animals injected with the candidate vaccine co-formulated with IL-18 showed a significant increase of Th1 immune response markers and an earlier increase of antibodies than those vaccinated without the cytokine. This suggests that IL-18 acts as an immunostimulant and vaccine adjuvant to boost the immune response against the antigens, reducing the therapeutic window of recombinant protein-based vaccines.

In vitro evaluation of the immunomodulatory activity of the nutraceutical formulation AminoDefence

Immune system (IS) functionality is warranted by inter-dependent processes that balance body defences without exceeding in inflammation. An ideal nutraceutical approach should sustain the protective IS activity while controlling inflammation. The potential immunomodulatory activity of the food supplement (FS) AminoDefence was studied in resting macrophages RAW264.7 and following stimulation of bacterial- and viral-associated inflammation trough LPS and PolyI:C treatments, respectively. In unstimulated macrophages, the formulation exerted a dose-dependent immunostimulant activity by up-regulating NO, IL-6, TNF-α and MCP-1 release, while it dampened the aberrant release of these factors induced by pro-inflammatory stimuli. Exploring the contribution of single components Echinacea purpurea (E. purpurea) extract and quercetin, used at proportional concentrations than in whole formulation, a more pronounced immunostimulant effect was observed for E. purpurea, and an anti-inflammatory activity for quercetin. Hence, AminoDefence exerts an immunomodulatory activity in macrophages by effectively stimulating a protective inflammatory response and limiting it in cases of excessive inflammation.

Effect of modification methods on the physical properties and immunomodulatory activity of particulate β-glucan.

β-Glucan is an immunoenhancing agent whose biological activities are linked to molecular structure. On that basis, the polysaccharide can be physiochemically modified to produce valuable functional materials. This study investigated the physical properties and immunostimulatory activity of modified β-glucan. Alkali-treated β-glucan had a distinct shape and smaller particle size than untreated β-glucan. The reduced particle size was conducive to the stability of the suspension because the β-glucan appeared to be completely dissolved by this treatment, forming an amorphous mass. Furthermore, alkali treatment improved the immunostimulating activity of β-glucan, whereas exposure of macrophages to heat-treated β-glucan decreased their immune activity. β-Glucan with reduced particle size by wet-grinding also displayed immunomodulatory activities. These results suggested that the particle size of β-glucan is a key factor in β-glucan-induced immune responses of macrophages. Thus, the modification of the β-glucan particle size provides new opportunities for developing immunoenhancing nutraceuticals or pharmacological therapies in the future.

Immunostimulant Compounds Identification in Indonesian Underutilized Zingiberaceae Spices

Spices are known for its health beneficial effect beside its function as flavouring and condiment. This study aimed to screen immunostimulant activities of 12 underutilized species of Zingiberaceae grown in Indonesia. The compound associated with immunostimulant activity in the most active sample was identified by linking the chromatogram profile of hexane, chloroform, ethyl acetate, methanol, and water fractions of the selected spices to its activity using orthogonal projection to the least square (OPLS) analysis, followed by LC-MS characterization. The result showed that Alpinia malaccensis and Zingiber ottensii had the highest lymphocyte cell proliferation index (SI) at concentrations of 400 ppm. A. malaccensis was chosen for the next step. The results of OPLS analysis showed that the retention time interval which strongly correlated with the immunostimulant activity was 27.0 – 28.5 minutes, which were abundant in methanol fraction. The mass spectra analysis of methanol fraction using UHPLC-HRMS showed that the respective retention time was attributed to flavokawain B. This compound was reported to increase rat splenocyte proliferation in vivo.

MRNAs encoding self-DNA reactive cGAS enhance the immunogenicity of lipid nanoparticle vaccines.

Nucleic acid-based vaccines hold promise in preventing infections and treating cancer. The most common use of this technology is to encode antigenic proteins on mRNAs that are delivered to cells via lipid nanoparticle (LNP) formulations. In this study, we discovered that immunostimulatory proteins can also be encoded on mRNAs in LNPs. We found that an active mutant of the enzyme cGAS, referred to as cGAS∆N, acts as a catalytic adjuvant in LNP-encapsulated mRNA vaccines. The delivery of cGAS∆N mRNA via LNPs in combination with antigen mRNA-LNPs led to durable antigen-specific IFNγ-producing T cells that exceeded the efficiency of antigen-LNPs similar to those currently used in the clinic. This strategy did not compromise B cell responses; rather it induced Th1-biased antibody isotypes. This work unveils new vaccine design strategies using mRNA-encoded catalytic adjuvants that could be ideal for generating CD8+ T cell and B cell responses for immunotherapies.

Elucidation of the Tissue Distribution and Host Immunostimulatory Activity of Exogenously Administered Probiotic-Derived Extracellular Vesicles for Immunoadjuvant.

Extracellular vesicles (EVs) are cell-derived nanoparticles that can be used as novel biomaterials. In the development of EVs-based therapeutic systems, it is essential to understand the in vivo fate of exogenously administered EVs and subsequent biological responses mediated by EVs. Although probiotics and microorganisms that modulate the host immune system also secrete EVs, their tissue distribution and biological reactions after administration to the host have not been sufficiently elucidated. In this study, we characterized EVs released from the probiotics Bifidobacterium longum (B-EVs) and Lactobacillus plantarum WCFS1 (L-EVs) in terms of tissue distribution and immune-activating capacity after intravenous and subcutaneous administration in mice. B-EVs and L-EVs exhibited particle sizes of approximately 100-160 nm and negative zeta potentials. These EVs contained peptidoglycan, DNA, and RNA as their cargoes. Intravenously administered B-EVs and L-EVs mainly accumulated in the liver and spleen. Furthermore, liver F4/80 and splenic CD169 macrophages took up the intravenously administered EVs. Subcutaneously administered B-EVs and L-EVs accumulated in the lymph nodes and were mainly located in the B-lymphocyte zone, indicating that exogenously administered probiotic-derived EVs showed a similar biodistribution, irrespective of the EVs-secreting cell type. Evaluation of EVs-mediated immune reactions demonstrated that intravenously administered EVs showed little activation potency. In contrast, subcutaneously administered B-EVs strongly increased the expression of inflammatory cytokine (TNF-α) and co-stimulatory molecules (CD40 and CD80) than L-EVs. These findings indicate that the subcutaneous administration of B-EVs is a useful strategy for the development of novel EVs-based immunotherapies.

Control of A/D type CpG-ODN aggregates to a suitable size for induction of strong immunostimulant activity

Among several types of CpG-ODNs, A/D-type CpG-ODNs have potent adjuvant activity to induce Th-1 immune responses, but exhibit a propensity to aggregate. For the clinical application of A/D-type CpG-ODNs, it is necessary to control such aggregation and obtain a comprehensive understanding of the relationship between their structure and the immune responses. This study revealed that a representative A/D-type CpG ODN, D35, adopted a single-stranded structure in water, while it assembled into aggregates in response to Na+ ions. From polyacrylamide gel electrophoresis and circular dichroism analyses, D35 adopted a homodimeric form (duplex) via palindromic sequences in low-Na+-concentration conditions (10–50 mM NaCl). After replacement of the solution with PBS, quadruplexes began to form in a manner coordinated by Na+, resulting in large aggregates. The duplexes and small aggregates prepared in 50 mM NaCl showed not only high cellular uptake but also high affinity to Toll-like receptor 9 (TLR9) proteins, leading to the production of a large amount of interferon-α for peripheral blood mononuclear cells. The much larger aggregates prepared in 100 mM NaCl were incorporated into cells at a high level, but showed a low ability to induce cytokine production. This suggests that the large aggregates have difficulty inducing TLR9 dimerization, resulting in loss of the stimulation of the cells. We thus succeeded in inducing adequate innate immunity in vitro by controlling and adjusting the formation of D35 aggregates. Therefore, the findings in this study for D35 ODNs could be a vital research foundation for in vivo applications.

A missing jigsaw within the hygiene hypothesis: Low-dose bisphenol A exposure attenuates lipopolysaccharide-induced asthma protection.

The rising occurrence of allergic asthma in early life across industrialized countries suggests that environmental factors play a crucial role in determining asthma susceptibility and severity. While prior exposure to microbial lipopolysaccharides (LPSs) has been found to offer protection against allergic asthma, infants residing in urban environments are increasingly exposed to environmental pollutants. Utilizing limulus lysate test screens and virtual screening models, we identified pollutants that can modulate LPS bioactivity. This investigation revealed that bisphenol A (BPA), a chemical commonly used in numerous household items and previously implicated in obesity and cancer, effectively neutralizes LPS. In-depth mechanistic analyses showed that BPA specifically binds to the lipid A component of LPS, leading to inactivation. This interaction eliminates the immunostimulatory activity of LPS, making mice more susceptible to house dust mite (HDM)-induced allergic asthma. BPA reactivates lung epithelial cells, consequently amplifying type 2 responses to HDMs in dendritic cells. This chemical interplay provides new insights into the pathophysiology of asthma in relation to human exposure. Understanding the intricate relationships between environmental chemicals and microbial antigens, as well as their impacts on innate immunity, is critical for the development of intervention strategies to address immune disorders resulting from urbanization.

Development of microneedles for propolis delivery: The effect on the production of reactive oxygen species and in vitro immunostimulating activity

Development of microneedles for propolis delivery: The effect on the production of reactive oxygen species and in vitro immunostimulating activity

Pharmacological and Medicinal Important of Plant Phyllanthus Emblica Linn. (Syn.Emblica Officinalis), Indian Gooseberry

Abstract: The plant names phyllanthus emblica linn (Amla) are very precious gift of nature which have a vital role in health care. Nowadays, use of herbal product become most important for humans over the world. This drug is very useful for the treatment of disease. The most important part of this plant (phyllanthus emblica) is fruit. Phyllanthus emblica Linn. (syn. Emblica officinalis), commonly known as Indian gooseberry or amla, belongs to the family Euphorbiaceae. Though all parts of the plant are used for medicinal purposes, the fruits especially are found tremendous pharmacological applications. They are highly nutritious and form an important dietary source of vitamin C, amino acids, and minerals. Emblica Officinalis Plant is reported to have diverse Pharmacological actions like Adaptogenic Activity, Hepatoprotective Activity, Anti-Bacterial Activity, Anti-Hyperlipidemia Activity, Hypolipidemic Activity, Anti-Atherogenic Activity, Immunostimulatory Activity, Anti-oxidant Activity, Anti-Tumor Activity,Anti-Microbial Activity,Chondroprotective Activity, Analgesic Activity, Anti-Inflammatory Activity & AntiDiarreheal Activity. Emblica Officinalis plant is used in the treatments of various ailments. The diverse ailments like cancer, Atherosclerosis, Inflammation, Osteoporosis, Nuerological disorders, Hypertention and other infectious disorders.

Structural characterization and immunomodulatory activity of an acidic polysaccharide from walnut green husk

Acidic walnut green husk polysaccharide with weight average molecular weight of 5.101 kDa was isolated and designated WGHP-2, which was composed of galacturonic acid (69.47 %), galactose (11.18 %), rhamnose (8.67 %), arabinose (3.96 %), glucose (2.21 %), glucuronic acid (2.28 %), xylose (0.83 %), fucose (0.81 %) and mannose (0.59 %). The main glycosidic linkage types of WGHP-2 were → 4-α-D-Glcp-(1→, →4-α-D-GalpA-(1→, t-β-D-GlcpA-(1→, →2-β-D-Rhap-(1→, t-α-D-Galp-(1→, →4-α-D-Galp-(1 → and → 2,4)-α-D-Manp(1 →. Immunostimulating assays showed that WGHP-2 could significantly promote the proliferation of RAW264.7 cells, strengthen the phagocytic activity, and up-regulate the production and release of NO, ROS, TNF-α, INF-β and IL-6. Western-blot analysis indicated that MAPK and PI3K/Akt pathways were involved in the activation of macrophages induced by WGHP-2. Overall, our study suggests that WGHP-2 has the potential to be developed as a functional food with good immunostimulatory activity.

Cnidium officinale polysaccharide enhanced RAW 264.7 cells activation and NK-92 cells cytotoxicity against colon cancer via NF-κB and MAPKs signaling pathways

In this study, Cnidium officinale-derived polysaccharides were isolated and investigated for their immune enhancing and anticancer activities. The isolated crude and its fractions, such as F1 and F2, contain carbohydrates (51.3–63.1%), sulfates (5.4–5.8%), proteins (1.5–7.1%), and uronic acids (2.1–26.9%). The molecular weight (Mw) of the polysaccharides ranged from 59.9 to 429.0 × 103 g/mol. The immunostimulatory activity of the polysaccharides was tested on RAW 264.7 cells, and the results showed that the F2 treatment notably enhanced pro-inflammatory activity in RAW 264.7 cells by increasing NO production and the expression of various cytokines. Furthermore, the influence of polysaccharide treatment on natural killer cells (NK-92) anticancer activities was investigated using a colon cancer cell line (HCT-116). Crude polysaccharide and its fractions showed no direct cytotoxicity to NK-92 and HCT-116 cells. However, the treatment of F2 showed an enhancement of NK-92 cells cytotoxicity against HCT-116 cells by upregulating the mRNA expression of IFN-γ, TNF-α, NKGp44, and granzyme-B. The western blot results showed that the induced RAW 264.7 cells activation and NK-92 cells cytotoxicity occur via NF-κB and MAPK signaling pathways. Overall, C. officinale-derived polysaccharides show potential as immunotherapeutic agents capable of enhancing pro-inflammatory macrophage signaling and activating NK-92 cells; thus, they could be useful for biomedical applications.

Evaluation of Immunomodulatory activity of phytochemicals from Alpinia galanga and Alpinia nigra for potent immunostimulatory agent in chemotherapy

Essential oils are capable of retaining vital medicinal benefits, however, there is a void in the research of biological activities of these oils in complex human disease models which is yet to be validated. For more explorations, we evaluated the medicinal activities of essential oil of A.galanga and A.nigra in order to find potent source of bioactive molecules, cytotoxicity and immuno stimulating activities of the essential oils from the rhizomes. We report immuno stimulating potential of these essential oils. Cytotoxicity of essential oil was evaluated using 3-(4,5-dimethythiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) assay to evaluate the toxicity against normal human peripheral blood mononuclear cells (PBMCs). The immunostimulatory activity on human lymphocytes was evaluated by using Th1 and Th2 cytokine estimations. Analysis of these essential oils through GC-MS revealed high content of 1, 8-cineole in both the oils (28.12% in A.galanga and 24% in A.nigra ). Both the rhizome oils showed significant increase in the number of lymphocytes than that of the control. The oils of A.galanga and A.nigra showed proliferative action on human PBMCs and an increase in both IL-5 and IFN-γ cytokine. As a result, no toxicity was recorded on human PBMCs. Major concentrations of 1,8-cineole and collaborative effects of the total composition of the rhizome oils were possibly accountable for the efficacy of these oils against human PBMCs. These essential oils can be considered as potential source of natural immunostimulatory agent in chemotherapy and also play important role in other immune suppressed diseases.

A Phase Ⅱ Study of Ubenimex Combined With Pembrolizumab, Nab-Paclitaxel, and Carboplatin for Previously Untreated Advanced Squamous Non–Small-Cell Lung Cancer: TORG2241 (UBE-Q)

BackgroundAccording to the results of the KEYNOTE-407 trial, pembrolizumab plus platinum-based chemotherapy is the standard of care for patients with previously untreated advanced squamous non–small-cell lung cancer (NSCLC). Ubenimex, a potent aminopeptidase inhibitor, is an oral drug with immunostimulatory and antitumor activities. We aim to assess the safety and efficacy of ubenimex in combination with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. Patients and MethodsThis prospective, single-arm, multicenter, phase II clinical trial is conducted to confirm the tolerability and efficacy of the tested drugs. Patients with previously untreated advanced squamous NSCLC will receive a predetermined daily dose of ubenimex orally plus 4 cycles of pembrolizumab, nab-paclitaxel, and carboplatin, followed by continuous administration of ubenimex and pembrolizumab for a maximum of 2 years. To confirm tolerability, the daily dose of ubenimex will begin at level 1 (30 mg), which will be increased to levels 2 (60 mg) and 3 (120 mg) according to the escalation criteria, with a standard 3 + 3 design for achieving the target dose-limiting toxicity rate of 33%. The efficacy, safety, and tolerability of ubenimex at the determined dose level will be analyzed. The primary endpoint of the efficacy evaluation will be the objective response rate assessed by an independent review committee. ConclusionsThis is the first study to evaluate the efficacy and safety of ubenimex combined with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. The results will help devise future treatment strategies.

The Dual Role of the Innate Immune System in the Effectiveness of mRNA Therapeutics.

Advances in molecular biology have revolutionized the use of messenger RNA (mRNA) as a therapeutic. The concept of nucleic acid therapy with mRNA originated in 1990 when Wolff et al. reported successful expression of proteins in target organs by direct injection of either plasmid DNA or mRNA. It took decades to bring the transfection efficiency of mRNA closer to that of DNA. The next few decades were dedicated to turning in vitro-transcribed (IVT) mRNA from a promising delivery tool for gene therapy into a full-blown therapeutic modality, which changed the biotech market rapidly. Hundreds of clinical trials are currently underway using mRNA for prophylaxis and therapy of infectious diseases and cancers, in regenerative medicine, and genome editing. The potential of IVT mRNA to induce an innate immune response favors its use for vaccination and immunotherapy. Nonetheless, in non-immunotherapy applications, the intrinsic immunostimulatory activity of mRNA directly hinders the desired therapeutic effect since it can seriously impair the target protein expression. Targeting the same innate immune factors can increase the effectiveness of mRNA therapeutics for some indications and decrease it for others, and vice versa. The review aims to present the innate immunity-related 'barriers' or 'springboards' that may affect the development of immunotherapies and non-immunotherapy applications of mRNA medicines.

Thermostability and Immunostimulatory Activity of Cationic Liposome-based Newcastle Disease Virus Vaccine

Cold storage is a huge challenge in maintaining vaccine potency especially in low and middle income countries (LMIC). The aim of this research was to investigate the heat and freeze-thaw stability of Newcastle disease virus (NDV) vaccine encapsulated in 1,2-dioleoyl-3-trimethyl ammonium propane (DOTAP) cationic liposomes as well as its immunostimulatory activity. DOTAP cationic liposomes were prepared using the thin-film hydration technique and characterized for morphology, particle size, polydispersity index, zeta potential and encapsulation efficiency. Experimental birds were challenged with Herts 33 velogenic strain of NDV. Haemagglutination inhibition test was used to assess the formation of antibodies in the birds. The cationic liposomes were further stored at 28 oC or subjected to freeze-thaw cycles for 7 weeks and then assessed for stability using the same parameters of particle size, polydispersity index, zeta potential, morphology, antibody titre or differential white blood cell count. Using TEM, the morphology of the liposomes was found to be spherical, and using Malvern Zetasizer, particle size was in the nanosize range. Zetapotential and polydispersity indices were positive and below 0.1. The HI test showed that the DOTAP cationic liposomes stimulated a higher titre of antibodies than the commercial vaccine. Heat and freeze-thaw stability studies after 7 weeks of storage showed slight aggregation and elevated particle sizes and wider distribution. The HI titer was appreciably lower after secondary immunization with the DOTAP cationic liposomes stored at 28 oC but elevated for the product kept at freeze-thaw conditions. The immunized birds were 100 % protected from the virulent strain of NDV. In conclusion, the development of the DOTAP-cationic liposomes encapsulating NDV vaccine administered orally was found to be more stable under freeze-thaw conditions than when it was exposed to heat for 7 weeks. The liposome-based vaccine had more immunostimulatory effects than the commercial sample.

Application of rhein as an immunostimulant controls spring viremia of carp virus infection

In recent years, the exploration of natural compounds possessing both immunostimulatory and antiviral activities has attracted growing attention in aquaculture research. Consequently, the pursuit of identifying natural products exhibiting anti-SVCV potential as immunostimulants holds significant promise, offering a pathway to mitigate the economic ramifications inflicted by SVCV outbreaks in aquaculture settings. Among them, rhein emerges as a particularly compelling contender. Boasting a widespread distribution, well-established extraction methods, and multiple biological activities, it has exhibited the capacity to enhance the antiviral activity of host cells in vitro by blocking the viral internalization process, with a peak inhibition rate of 44.0%. Based on this intervention, rhein inhibited apoptosis and mitochondrial damage triggered by SVCV infection, ultimately producing a significant antiviral effect. Moving beyond the laboratory setting, rhein's efficacy translates effectively into in vivo scenarios. It has demonstrated substantial antiviral potency by increasing the expression of antiviral-related genes, most notably, retinoic acid-inducible gene I (RIG-I), interferon-φ (IFN-φ) and IFN-stimulated gene product 15 (ISG15). In concert with this genetic modulation, rhein efficiently reduces the viral load, precipitating a consequential enhancement in the survival rate of SVCV-infected fish, elevating it to an encouraging 16%. In conclusion, the outcomes of our investigation offer a compelling testament to rhein's potential as a valuable immunomodulator in the battle against SVCV infections in aquaculture, and the remarkable attributes exhibited by rhein underscore its viability for future commercial deployment.

Purification and characterization of a novel immunoregulatory peptide from Sipunculus nudus L. protein.

This study aimed to purify and characterize immunoregulatory peptides from Sipunculus nudus L. and to explore the underlying mechanisms. Ultrafiltration, gel filtration chromatography, and reverse phase high-performance liquid chromatography (RP-HPLC) were used to purify the peptide following enzymatic hydrolysis. Rates of lymphocyte proliferation and phagocytosis as well as nitric oxide (NO) production levels were used as indicators of immunoregulatory activity to screen the fractions. The amino acid sequence of the peptide, designated as SNLP, was identified as Arg-Val-Lys-Gly-Lys-Ile-Leu-Ala-Lys-Arg-Leu-Asn (RVKGKILAKRLN) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Treatment with the synthetic SNLP increased the proliferation and phagocytosis of RAW 264.7 macrophages and promoted the secretion of tumor necrosis factor-ɑ (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and NO levels. The mRNA levels of these cytokines and iNOS were also increased by SNLP. Our results provide preliminary evidence suggesting that SNLP acts as a dual immunomodulatory peptide with immunostimulatory and anti-inflammatory activities. In summary, SNLP derived from Sipunculus nudus L. is a potent immunoregulatory peptide and represents a potential functional food or immunoregulatory drug.

Aminated yeast β-D-glucan for macrophage-targeted delivery of CpG oligodeoxynucleotides and synergistically enhanced cancer immunotherapy

CpG oligodeoxynucleotides (CpG ODNs) activate immune system and show strong potential in cancer immunotherapy. However, therapeutic efficacy of CpG ODNs is hampered due to rapid nuclease degradation and insufficient cellular uptake. Delivery of CpG ODNs into antigen presenting cells (APCs) is vital to enhance their therapeutic efficacy. Herein, we developed a super-convenient yet efficient strategy for macrophage-targeted delivery of CpG ODNs and synergistically enhanced cancer immunotherapy. Aminated yeast β-D-glucan (NH2-Glu) was simply synthesized through functionalization of β-D-glucan with DETA, which exhibited a dendrimer-like shape with size of about 80 nm. NH2-Glu complexed negatively-charged CpG ODNs. The as-prepared NH2-Glu/CpG complexes were positively charged, uniformly dispersed and exhibited good stability against nuclease degradation. Due to the specific recognition with dectin-1 expressed on macrophages, NH2-Glu/CpG complexes targeted macrophage and exhibited significantly enhanced cellular uptake due to dectin-1-mediated endocytosis. NH2-Glu/CpG complexes showed potent immunostimulatory activity. Contributed by the inherent immunostimulatory and antitumor activity, yeast β-D-glucan functioned synergistically with CpG ODNs in inducing antitumor immunity. NH2-Glu/CpG complexes remarkably inhibited tumor growth without causing toxic effect. In summary, this work provides a facile yet efficient macrophage-targeted CpG ODNs delivery system for cancer immunotherapy.