Effective cancer immune therapy requires the orchestration of antigen induction, presentation and T-cell activation, further enhanced by anti-angiogenesis treatment; therefore, multiple therapeutics are generally used for such combination therapy. Herein, we report esterase-hydrolysable cationic polymers, N-[3-((4-acetoxy benzyl) oxy)-3-oxopropyl]-N-methyl-quaternized PEI (ERP) and poly{N-[2-(acryloyl-oxy) ethyl]-N-[p-acetyloxyphenyl]-N,N-dimethylammonium chloride} (PQDMA), capable of simultaneously inducing tumor cell immunogenic cell death (ICD) to release antigens, activating the cGAS-STING pathways of tumor macrophages and dendritic cells, and releasing antiangiogenic agent p-hydroxybenzyl alcohol (HBA). Thus, intratumoral injection of ERP or PQDMA systemically boosted the anti-cancer immunities and inhibited tumor angiogenesis in mouse hepatocellular carcinoma and melanoma bilateral tumor models, leading to more effective tumor growth inhibition of both treated and abscopal untreated tumors than ICD alone induced by mitoxantrone and control cationic polymers. Further study using gene knockout mice and transcriptome sequencing analysis confirmed the involvement of cGAS-STING and type I IFN signaling pathways. This work demonstrates ERP and PQDMA as the first examples of inherent therapeutic polymers, accomplishing systemic tumor inhibition without combining other therapeutic agents.

Vaccines based on mRNA have been fundamental in facing the COVID-19 pandemic, however, they still raise concerns about stability and long-term efficacy. Thus, protein-based vaccines remain valid options and hence the study of effective adjuvants is crucial. Here, we developed a COVID-19 vaccine based on the receptor-binding domain (RBD) of SARS-CoV-2 Spike protein, which is covalently conjugated to the natural polymer hyaluronan (HA) that acts as an immunological adjuvant. Vaccination of K18-hACE2 mice with HA-RBD was well tolerated, and elicited high and sustained titres of RBD-binding antibodies and SARS-CoV-2-neutralizing antibodies, without the addition of other immunostimulatory compounds. Most importantly, HA-RBD vaccination conferred long-term protection to K18-hACE2 mice after challenge with SARS-CoV-2, also in the case of two consequent infections driven by different variants. These findings demonstrate the efficacy of HA-based vaccination against COVID-19 disease, and support the promising use of HA as an efficient and well tolerated adjuvant.

Activation of the cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes (STING) has great potential to promote antitumor immunity. As a major effector of the cell to sense and respond to the aberrant presence of cytoplasmic double-stranded DNA (dsDNA), inducing the expression and secretion of type I interferons (IFN) and STING, cGAS-STING signaling pathway establishes an effective natural immune response, which is one of the fundamental mechanisms of host defense in organisms. In addition to the release of heterologous DNA due to pathogen invasion and replication, mitochondrial damage and massive cell death can also cause abnormal leakage of the body's own dsDNA, which is then recognized by the DNA receptor cGAS and activates the cGAS-STING signaling pathway. However, small molecule STING agonists suffer from rapid excretion, low bioavailability, non-specificity and adverse effects, which limits their therapeutic efficacy and in vivo application. Various types of nano-delivery systems, on the other hand, make use of the different unique structures and surface modifications of nanoparticles to circumvent the defects of small molecule STING agonists such as fast metabolism and low bioavailability. Also, the nanoparticles are precisely directed to the focal site, with their own appropriate particle size combined with the characteristics of passive or active targeting. Herein, combined with the cGAS-STING pathway to activate the immune system and kill tumor tissues directly or indirectly, which help maximize the use of the functions of chemotherapy, photothermal therapy(PTT), chemodynamic therapy(CDT), and radiotherapy(RT). In this review, we will discuss the mechanism of action of the cGAS-STING pathway and introduce nanoparticle-mediated tumor combination therapy based on the STING pathway. Collectively, the effective multimodal nanoplatform, which can activate cGAS-STING pathway for enhanced anti-tumor immunotherapy, has promising avenue clinical applications for cancer treatment.

Effective subunit vaccine development requires selecting appropriate adjuvant formulations to trigger desired adaptive immune responses. This study explores the immunogenicity and tuberculosis (TB) vaccine potential of antigens (Ags) combined with Toll-like receptor 4 (TLR4) adjuvants and a stimulator of interferon genes (STING) agonist.

In this work, we investigated the combination of Ags with TLR4 adjuvants (monophosphoryl lipid A / dimethyldioctadecylammonium bromide; MPL/DDA or glucopyranosyl lipid adjuvant-stable emulsion; GLA-SE) and a STING agonist, c-di-GMP (CDG). Mice were immunized three times by intramuscular injections at 3-week intervals. The effects of integrating Ags in these adjuvant formulations on the immune response were evaluated, focusing on the generation of Th1-biased, polyfunctional Ag-specific CD4+ T cells and their localization in the lung and spleen. To assess protection, immunized mice were aerogenically challenged with either conventional or ultra-low doses of Mycobacterium tuberculosis (Mtb) 4 weeks after the last immunization. Subsequently, bacterial load and pulmonary inflammation were assessed.

Integrating ESAT6 Ag in TLR4 and CDG adjuvant formulations remarkably boosted Th1-biased, polyfunctional ESAT6-specific CD4+ T cells in the lungs and spleen, providing durable protection against Mtb infection. The inclusion of CDG promoted mucosal localization of ESAT6-specific CD4+ T cells resembling resident memory phenotypes in the lung parenchyma and increased Ag-specific CD4+ T cells in lung vasculature. Immunization with another vaccine Ag candidate, Ag85B, in GLA-SE plus CDG similarly increased Ag85B-specific CD4+ T cells in the spleen and both lung compartments. Following ultra-low dose Mtb challenge, ESAT6 or Ag85B/GLA-SE/CDG immunizations significantly reduced bacterial loads compared to non-, Bacillus Calmette-Guérin (BCG)-, and ESAT6 or Ag85B/GLA-SE-immunized groups. Importantly, the inclusion of CDG decreased killer cell lectin-like receptor subfamily G member 1 (KLRG1) expression among Ag-specific CD4+ T cells in the lung, correlating with enhanced lung-homing evidenced by expanded lung parenchyma Ag-specific CD4+ T cells, including less-differentiated Th1 cells.

This study highlights that CDG, when used in combination with TLR4 adjuvants, enhances long-term protective immunity, offering a promising strategy for subunit TB vaccine development.

Chitosan, derived from chitin, is frequently employed in various applications, including hydrogels. In cancer treatment, chitosan serves as a drug carrier, enhancing drug bioavailability while reducing side effects. Additionally, its inherent antibacterial properties and ability to maintain a moist environment facilitate faster wound healing. Its capacity for controlled drug release also ensures prolonged delivery of therapeutic agents. Furthermore, its biocompatibility and biodegradability present substantial advantages. Beyond conventional methods, chitosan is now being utilized as a bioink in 3D printing technologies. This innovation enables personalized treatments, leveraging the advantages of chitosan. However, certain challenges must be addressed to ensure the proper application of this technology. This review not only provides comprehensive insights into the synthesis and biomedical applications of chitosan hydrogels but also summarizes recent studies from the past five years, focusing on their roles in wound healing, cancer treatment, and 3D printing applications.

Detecting cytoplasmic or extracellular DNA from host or pathogen origin by DNA sensor cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) triggers immune responses with secretion of type I interferons and inflammatory cytokines. However, STING agonists function as type-2 adjuvant promoting allergic asthma. Here, we asked how cGAS/STING signaling pathway influences allergen-induced type-2 immune responses in models of allergic airway diseases induced by birch pollen extract, house dust mite, or ovalbumin plus Alum. We report increased extracellular dsDNA in the airways, together with cGAS and STING gene expression, following allergen challenge in these models, correlating dsDNA and type-2 cytokine IL-4, IL-5, and IL-13 release. Allergen-induced type-2 immune responses were reduced in cGAS- or STING-deficient mice. Further, blocking cGAS function with the specific inhibitor RU.521 protected mice from birch pollen allergen-induced airway inflammation and type-2 immune responses. Thus, DNA sensing by cGAS contributes to type-2 immune responses and may represent a therapeutic target for allergic lung inflammation.

Background/Objectives: Gene therapy has emerged as a promising strategy for treating a wide range of diseases. However, a major challenge remains in developing efficient and safe delivery systems for genetic material. Nanoparticles, particularly chitosan nanoparticles (CNPs), have gained significant attention as a potential solution. This study focuses on designing a SARS-CoV-2 plasmid DNA (pDNA) conjugated with CNPs and evaluating its in vitro delivery efficiency. Methods: The Omicron Spike DNA sequence was inserted into the pIRES2-eGFP expression vector, and CNPs were synthesized with optimized physicochemical properties to enhance stability, cellular uptake, and transfection efficiency. The conjugate was characterized using UV-Vis, FT-IR, DLS, and TEM techniques. Transfection efficiency was assessed and compared to the commercially available TurboFect reagent as a control. Results: CNPs-pDNA polyplexes with an average size of 159.0 ± 33.1 nm (TEM), a zeta potential of +19.7 ± 0.3 mV, and 100% ± 0.0 encapsulation efficiency were developed as a non-viral delivery system. CNPs efficiently serve as a delivery vehicle for the constructed pDNA without altering cell morphology, achieving transfection efficiencies of 62-74%, compared to 55-70% for TurboFect. Furthermore, RT-qPCR confirmed the expression of Spike mRNA, and Western blot assays validated the expression of Spike protein. Notably, Spike protein expression from CNPs was found to be two-fold higher than the control at 96 h post-transfection. Conclusions: These findings suggest that CNPs are a promising and versatile platform for delivering genetic material. Importantly, this study highlights the intrinsic properties of chitosan, without the use of additional ligands, as a key factor in achieving efficient gene delivery.

The success of biomaterial applications in medicine, particularly in tissue engineering, relies on achieving a balance between promoting tissue regeneration and controlling the immune response. Due to its natural origin, high biocompatibility, and versatility, chitosan has emerged as a promising biomaterial especially for immunomodulation purposes. Immunomodulation, refers to the deliberate alteration of the immune system's activity to achieve a desired therapeutic effect either by enhancing or suppressing the function of specific immune cells, signaling pathways, or cytokine production. This modulation opens up the unlimited possibilities for the use of biomaterials, especially about the use of natural polymers such as chitosan. Although numerous chitosan-based immunoregulatory strategies have been demonstrated over the past two decades, the lack of in-depth exploration hinders the full potential of strategies that include chitosan and its derivatives in biomedical applications. Thus, in this review, the possible immunomodulatory effects of chitosan, chitosan derivatives and their potential combined with various agents and therapies are investigated in detail. Moreover, this report includes agents for localized immune response control, chitosan-based strategies with complementary immunomodulatory properties to create synergistic effects that will influence the success of cell therapies for enhanced tissue acceptance and regeneration. Finally, the challenges and outlook of chitosan-based therapies as a powerful tool for improving immunomodulatory applications are discussed for paving the way for further studies.

The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome is pivotal in orchestrating the immune response induced by nanoparticle adjuvants. Understanding the intricate mechanisms underlying the activation of NLRP3 inflammasome by these adjuvants is crucial for deciphering their immunomodulatory properties. This review explores the involvement of the NLRP3 inflammasome in mediating immune responses triggered by nanoparticle adjuvants. It delves into the signaling pathways and cellular mechanisms involved in NLRP3 activation, highlighting its significance in modulating the efficacy and safety of nanoparticle-based adjuvants. A comprehensive grasp of the interplay between NLRP3 inflammasome and nanoparticle adjuvants holds promise for optimizing vaccine design and advancing immunotherapeutic strategies.

Sepsis, an inflammatory disease caused by bacterial infection, has become a global public health crisis. Excessive reactive oxygen species (ROS) in sepsis patients act as the primary trigger for activating intracellular immune pathways, ultimately leading to multiple organ dysfunction syndrome. The overexpression of acidic metabolites and ROS, characteristic of the infected microenvironment, significantly impedes sepsis treatment. Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, plays a key role in inflammatory diseases. The detrimental effects of STING in sepsis have been well documented. Here, we developed a pH-responsive nanotherapy platform (DMSNM@C-178/PAA) that combines ROS scavenging with cGAS-STING pathway inhibition for anti-inflammatory therapy. This nanoparticle is selectively released in the infected microenvironment, where reduced molybdenum-based polyoxometalates (Mo-POM) efficiently neutralize toxic ROS in vivo, while C-178 selectively inhibits the cGAS-STING pathway, thereby attenuating the inflammatory response and preventing organ deterioration. In vitro and in vivo studies demonstrate that DMSNM@C-178/PAA treats sepsis by eliminating excess ROS and modulating autoimmune dysfunction via the cGAS-STING pathway, providing a novel therapeutic strategy for sepsis management.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in triggering innate and adaptive immune responses through type I interferon activation and immune cell recruitment, holding significant promise for cancer therapy. While STING activators targeting this pathway have been developed, their clinical application is hindered by challenges such as poor membrane permeability, rapid degradation, suboptimal pharmacokinetics, off-target biodistribution, and toxicity. Nanoparticle-based delivery systems offer a promising solution by enhancing the stability, circulation time, tumor accumulation, and intracellular release of STING activators. Furthermore, combining nanoparticle-delivered STING activators with radiotherapy, chemotherapy, phototherapy, and other immunotherapies enables synergistic antitumor effects through multimodal mechanisms, addressing resistance to monotherapies and reducing risks of recurrence and metastasis. This review outlines the immunomodulatory mechanisms of the cGAS-STING pathway, surveys current STING-targeted activators, and comprehensively discusses recent advances in nanoparticle-mediated delivery strategies for STING activation. Additionally, we explore combinatorial approaches that integrate STING-targeted nanotherapies with conventional and emerging treatments. Finally, we highlight the current status, prospects, and challenges of nanoparticle-based STING activation for cancer immunotherapy.

Adjuvants, as a critical component of vaccines, are capable of eliciting more robust and sustained immune responses. Nanomaterials have shown unique advantages and broad application prospects in adjuvant development due to their high adjustability and distinctive physicochemical properties. This review focuses on nanoadjuvants and their immunological mechanisms. First, various types of adjuvants are introduced with an emphasis on metal and metal oxide nanoparticles, coordination polymers, liposomes, polymer nanoparticles, and other inorganic nanoparticles that can serve as vaccine adjuvants. Second, this review describes the current status of the clinical applications of nanoadjuvants. Next, the mechanisms of action for nanoadjuvants have been thoroughly elucidated, including the depot effect, NLRP3 inflammasome activation, targeting C-type lectin receptors, activation of toll-like receptors, and activation of the cGAS-STING signaling pathway. Finally, the challenges and opportunities associated with the development of nanoadjuvants have also been addressed.

The functionality and mechanism of bioactive agents (BA) in treating various diseases have been studied as a progressive route. Designing an effective delivery system for transferring these molecules and components is a major challenge. For that reason, a wide range of biomaterials has been introduced to deliver BA to the target tissue or cells. Chitosan (CTS) is a nontoxic, biocompatible, biodegradable, and notable point low-cost polymer, and, as a result, can be effectively utilized in the formulation of diverse delivery systems, in biomedical applications. However, CTS has some limitations, such as poor solubility in aqueous and alkaline media, rapid swelling and degradation, and consequence fast release agent. The CTS derivative carboxymethyl chitosan (CMC) is an acceptable candidate for overcoming these limitations. CMC is a high-impact grade for pharmaceutical and biomedical applications because of its nontoxic, biocompatible, biodegradable, gelation, mucoadhesive, antibacterial, and antifungal. CMC bioactivity potentials are related to carboxyl and methyl groups added through chemical modification in the CTS backbone. In this review, the physical and chemical properties of CTS and CMC have been introduced and discussed. Afterward, its biomedical applications with delivery approaches for various BA (drugs, genes, proteins), microfluidic, and cancer have been considered.

Folic acid has been associated with fetal development, especially in fetal immunity. Therefore, limited evidence regarding the effects of different folic acid supplementation of hepatitis B surface antigen (HBsAg) positive mothers in innate immunity in offspring. Herein, this study aimed to explore the association between folic acid supplementation and the innate immunity of neonates and the immunological efficacy of hepatitis B vaccine (HepB), which may provide insights that could inform pre-pregnancy health management in HBsAg-positive mothers.

It is an ambispective cohort study with 293 pairs of HBsAg-positive mothers-offspring in Taiyuan, Shanxi Province, China. Mothers were classified into three groups according to the time of starting folic acid supplementation, non-supplementation group, pre-pregnancy group and post-pregnancy supplementation group. Immunological indexes such as immune cells proportion and innate immune mediators in cord blood and anti-HBs in infants were measured. Differences in immunological indexes were analyzed by One-Way ANOVA test. Univariate and multivariate analyses were performed for factors associated with abnormal immunological indexes and potential confounders were adjusted.

The preconception folic acid group showed a significantly higher expression levels of STING (P = 0.005) and pNF-κB (P = 0.010) in cord blood along with higher anti-HBs titres (P = 0.006), when compared to both non-supplementation group and post-pregnancy supplementation group. Higher anti-HBs levels indicate a stronger immune response to HepB and may enhance protection against HBV infection during early life. Infants in the high pNF-κB expression group exhibited a significantly elevated seropositive rate of HepB compared to those in the low pNF-κB expression group (P = 0.037). There were no mediation effects and no moderation effects in this study, potentially due to the direct influence of folic acid supplementation on immune responses or the limited sample size.

In conclusion, our findings demonstrate that preconception folic acid supplementation may enhance HepB vaccine responsiveness in infants of HBsAg-positive mothers. Meanwhile, high pNF-κB expression in cord blood can increase seropositive rates in infants. This discovery has significant public health implications, as it may provide a simple and accessible intervention to improve vaccination outcomes and reduce HBV transmission in endemic regions.

The integration of nanotechnology into drug delivery systems holds great promise for enhancing pharmaceutical effectiveness. This approach enables precise targeting, controlled release, improved patient compliance, reduced side effects, and increased bioavailability. Nanoparticles are vital for transporting biomolecules-such as proteins, enzymes, genes, and vaccines-through various administration routes, including oral, intranasal, vaginal, buccal, and pulmonary. Among biodegradable polymers, chitosan, a linear polysaccharide derived from chitin, stands out due to its biocompatibility, safety, biodegradability, mucoadhesive properties, and ability to enhance permeation. Its cationic nature supports strong molecular interactions and provides antimicrobial, anti-inflammatory, and hemostatic benefits. However, its solubility, influenced by pH and ionic sensitivity, poses challenges requiring effective solutions. This review explores chitosan, its modified derivatives and chitosan nanoparticles mainly, focusing on nanoparticles physicochemical properties, drug release mechanisms, preparation methods, and factors affecting their mean hydrodynamic diameter (particle size). It highlights their application in drug delivery systems and disease treatments across various routes. Key considerations include drug loading capacity, zeta potential, and stability, alongside the impact of molecular weight, degree of deacetylation, and drug solubility on nanoparticle properties. Recent advancements and studies underscore chitosan's potential, emphasizing its modified derivatives'versatility in improving therapeutic outcomes.

Owing to its non-invasive nature, painless drug delivery, and controlled drug loading capacity, the microneedle (MN) technology has recently garnered significant attention in clinical practice. For instance, it has been pervasively employed as an innovative transdermal delivery method in skin disease therapy. However, traditional MN techniques have been associated with challenges regarding biocompatibility, biodegradability, and drug release precision, limiting their clinical efficacy and increasing the risk of side effects resulting from uneven drug distribution. To address these issues, polysaccharide materials have been proposed as viable alternatives to be used in MN technologies. In addition to their excellent biocompatibility and biodegradability, polysaccharide materials such as alginate, chitosan, and Hyaluronic Acid (HA), among other Traditional Chinese Medicine (TCM)-extracted polysaccharides (such as Bletilla and notoginseng), could also exert anti-inflammatory and antibacterial effects, promoting tissue regeneration. These attributes enable polysaccharide-based MNs to improve the local drug concentration, reduce systemic side effects, minimize patient discomfort, and lower treatment risks, making them particularly suitable for treating skin conditions such as eczema, psoriasis, and acne. This article systematically reviews the properties of various polysaccharide materials, as well as the preparation methods of polysaccharide-based MNs and their therapeutic effects as reported in animal models and clinical trials. Our findings could lay a solid theoretical foundation for developing polysaccharide-based MN technologies and fostering their widespread clinical application.

Nanovaccines, as a new generation of vaccines, have garnered significant interest due to their exceptional potential in enhancing disease prevention and treatment. Their unique features, such as high stability, antigens protection, prolonged retention, and targeted delivery to lymph nodes, immune cells, and tumors, set them apart as promising candidates in the field of immunotherapy. Polymers, with their superior degradability, capacity to mimic pathogen characteristics, and surface functionality that facilitates modifications, serve as ideal carriers for vaccine components. Polymer-based self-adjuvanted nanovaccines have the remarkable ability to augment immune responses. The inherent adjuvant-like properties of polymers themselves offer a pathway toward more efficient exploitation of nanomaterials and the optimization of nanovaccines. This review article aims to summarize the categorization of polymers and elucidate their mechanisms of action as adjuvants. Additionally, it delves into the advantages and limitations of polymer-based self-adjuvanted nanovaccines in disease management and prevention, providing valuable insights for their design and application. This comprehensive analysis could contribute to the development of more effective and tailored nanovaccines for a wide range of diseases.

Cancer is a major cause of death worldwide, and vaccine administration is an effective way to stimulate immune responses in patients and to achieve preventive and therapeutic effects. Few vaccines have been used in clinical settings because they have poor immunogenicity, and it is difficult to induce a robust immune response in patients. An adjuvant is an important component of a vaccine that can enhance the intensity, speed, and duration of immune responses. The achievements of adjuvants in the production of stable, safe, and immunogenic tumor vaccines have aroused the enthusiasm of researchers. Recent results have suggested that plant-derived adjuvants have unique advantages, such as greatly improving immune responses to cancer vaccines and promoting humoral and cellular immunity with good biocompatibility and biodegradability. When these adjuvants are used in combination with vaccines, they can not only activate the immune response in vivo but can also promote cytokine secretion and accelerate dendritic cell maturation. This review focused on the application progress of plant adjuvants, including saponins, polysaccharides, flavonoids, and plant virus-like particles, and their combination with nano-delivery systems in cancer vaccines. At the same time, we have also discussed the immunomodulatory mechanisms of these adjuvants and their prospects for improving vaccine efficacy in the treatment of cancer in the future. These promising plant adjuvants may provide prospects and a research basis for the development of tumor vaccines.

Vaccination is an effective strategy for preventing infectious diseases. Subunit vaccines offer more precise targeting and safer protection compared with traditional inactivated virus vaccines. However, due to their poor immunogenicity, subunit vaccines necessitate the use of adjuvants to stimulate the immune system. Adjuvants have long been incorporated into vaccines to enhance the body's immune response, allowing for reduced dosage and lower production costs. Despite the development of numerous vaccine adjuvants, few exhibit the necessary potency and low toxicity for clinical use, often due to limited efficacy or adverse side effects. This underscores the urgent need for novel human vaccine adjuvants that are safe, effective, and cost-efficient. Recent studies have identified certain natural polysaccharides as promising human vaccine adjuvants due to their immunostimulatory properties, low toxicity, and high safety profiles, which enhance both humoral and cellular immunity. These natural polysaccharides are primarily derived from traditional Chinese medicine (TCM) plants, bacteria, and yeast. This review comprehensively analyzes several promising polysaccharide adjuvants, discussing their clinical applications, market potential, and immunoregulatory activities. In summary, the future prospects of polysaccharides provide valuable insights for the application and development of vaccine adjuvants.

It has recently been recognized that the physical characteristics of biomaterials - such as size, structure, shape, charge, mechanical strength, hydrophobicity, and multivalency - regulate immunological functions in innate immune cells. In immuno-oncology applications, biomaterials are engineered with distinct physical properties to achieve desired innate immune responses. In this review, we discuss how physical characteristics influence effector functions and innate immune signaling pathways in distinct innate immune cell subtypes. We highlight how physical properties of biomaterials impact phagocytosis regulation, biodistribution, and innate immune cell targeting. We outline the recent advances in physical engineering of biomaterials that directly or indirectly induce desired innate immune responses for cancer immunotherapy. Lastly, we discuss the challenges in current biomaterial approaches that need to be addressed to improve clinical applicability.

Cancer immunotherapy, which leverages immune system components to treat malignancies, has emerged as a cornerstone of contemporary therapeutic strategies. Yet, critical concerns about the efficacy and safety of cancer immunotherapies remain formidable. Nanotechnology, especially polymeric nanoparticles (PNPs), offers unparalleled flexibility in manipulation-from the chemical composition and physical properties to the precision control of nanoassemblies. PNPs provide an optimal platform to amplify the potency and minimize systematic toxicity in a broad spectrum of immunotherapeutic modalities. In this comprehensive review, the basics of polymer chemistry, and state-of-the-art designs of PNPs from a physicochemical standpoint for cancer immunotherapy, encompassing therapeutic cancer vaccines, in situ vaccination, adoptive T-cell therapies, tumor-infiltrating immune cell-targeted therapies, therapeutic antibodies, and cytokine therapies are delineated. Each immunotherapy necessitates distinctively tailored design strategies in polymeric nanoplatforms. The extensive applications of PNPs, and investigation of their mechanisms of action for enhanced efficacy are particularly focused on. The safety profiles of PNPs and clinical research progress are discussed. Additionally, forthcoming developments and emergent trends of polymeric nano-immunotherapeutics poised to transform cancer treatment paradigms into clinics are explored.

Application of one-dimensional nanofibers have witnessed exponential growth over the past few decades and are still emerging with their excellent physicochemical and electrical properties. The driving force behind this intriguing transition lies in their unique high surface-to-volume ratio, ubiquitous nanodomains, improved tensile strength, and flexibility to incorporate deliberate functionalities required for specific and advanced applications. Besides numerous benefits, nanomaterials may adversely interact with biological tissues and potentially be cytotoxic and carcinogenic. However, precisely engineered design can outperform the risk with myriad benefits. Wound care technologies are evolving, and products involved in wound care management have a yearly market value of $15-22 billion. Solution blow spinning (SBS) is a facile technique to synthesize biocompatible nanofibers with scalable processing variables for multidirectional biomedical applications. SBS is feasible for a wide range of thermoplastic polymers and nanomaterials to fabricate nanocomposites. This review will focus on the relevance of SBS technology for wound care, including dressings, drug delivery, tissue engineering scaffolds, and sensors.

Utilizing the cGAS-STING pathway to combat immune evasion is one of the most promising strategies for enhancing cancer immunotherapy. However, current techniques for activating the cGAS-STING pathway often face a dilemma, mainly due to the balance between efficacy and safety. Here, we develop a uracil base lesion-gated dumbbell DNA nanodevice (UBLE) that allows on-demand activation and termination of the cGAS-STING pathway in tumor cells, thereby enhancing cancer immunotherapy. The UBLE integrates two deoxyuridines (dU) in the stem for DNA lesion recognition, two locked complementary primer sequences (primers A and B) for DNA self-assembly, and a Förster resonance energy transfer pair (Cy3 and Cy5) attached to the loop for activation assessment. Upon the orthogonal recognition of tumor-specific repair indicators (UDG and APE1), the UBLE undergoes a conformational change to create massive nicked double-stranded DNA (dsDNA) units. These units self-assemble to generate long fluorescent dsDNA structures, permitting selective evaluation and on-demand activation of the cGAS-STING pathway. Furthermore, we demonstrate that the UBLE can effectively activate the cGAS-STING pathway in tumor cells, enhancing NK cell-targeted cancer immunotherapy. This work develops a DNA lesion-gated strategy for on-demand activation and termination of the cGAS-STING pathway, affording an innovative avenue for enhancing cancer immunotherapy.

Background/Objective: Cationic polymers were shown to assemble with negatively charged proteins yielding nanoparticles (NPs). Poly-diallyl-dimethyl-ammonium chloride (PDDA) combined with ovalbumin (OVA) yielded a stable colloidal dispersion (OVA/PDDA-NPs) eliciting significant anti-OVA immune response. Dendritic cells (DCs), as sentinels of foreign antigens, exert a crucial role in the antigen-specific immune response. Here, we aimed to evaluate the involvement of DCs in the immune response induced by OVA/PDDA. Methods: In vivo experiments were used to assess the ability of OVA/PDDA-NPs to induce anti-OVA antibodies by ELISA, as well as plasma cells and memory B cells using flow cytometry. Additionally, DC migration to draining lymph nodes following OVA/PDDA-NP immunization was evaluated by flow cytometry. In vitro experiments using bone marrow-derived DCs (BM-DCs) were used to analyze the binding and uptake of OVA/PDDA-NPs, DC maturation status, and their antigen-presenting capacity. Results: Our data confirmed the potent effect of OVA/PDDA-NPs inducing anti-OVA IgG1 and IgG2a antibodies with increased CD19+CD138+ plasma cells and CD19+CD38+CD27+ memory cells in immunized mice. OVA/PDDA-NPs induced DC maturation and migration to draining lymph nodes. The in vitro results showed higher binding and the uptake of OVA/PDDA-NPs by BM-DCs. In addition, the NPs were able to induce the upregulation of costimulatory and MHC-II molecules on DCs, as well as TNF-α and IL-12 production. Higher OVA-specific T cell proliferation was promoted by BM-DCs incubated with OVA/PDDA-NPs. Conclusions: The data showed the central role of DCs in the induction of antigen-specific immune response by OVA-PDDA-NPs, thus proving that these NPs are a potent adjuvant for subunit vaccine design.

Cancer is one of the leading causes of mortality around the world and most of our conventional treatments are not efficient enough to combat this deadly disease. Harnessing the power of the immune system to target cancer cells is one of the most appealing methods for cancer therapy. Nucleotide-based cancer vaccines, especially deoxyribonucleic acid (DNA) cancer vaccines are viable novel cancer treatments that have recently garnered significant attention. DNA cancer vaccines are made of plasmid molecules that encode tumor-associated or tumor-specific antigens (TAAs or TSAs), and possibly some other immunomodulatory adjuvants such as pro-inflammatory interleukins. Following the internalization of plasmids into cells, their genes are expressed and the tumor antigens are loaded on major histocompatibility molecules to be presented to T-cells. After the T-cells have been activated, they will look for tumor antigens and destroy the tumor cells upon encountering them. As with any other treatment, there are pros and cons associated with using these vaccines. They are relatively safe, usually well-tolerated, stable, easily mass-produced, cost-effective, and easily stored and transported. They can induce a systemic immune response effective on both the primary tumor and metastases. The main disadvantage of DNA vaccines is their poor immunogenicity. Several approaches including structural modification, combination therapy with conventional and novel cancer treatments (such as chemotherapy, radiotherapy, and immune checkpoint blockade (ICB)), and the incorporation of adjuvants into the plasmid structure have been studied to enhance the vaccine's immunogenicity and improve the clinical outcome of cancer patients. In this review, we will discuss some of the most promising optimization strategies and examine some of the important trials regarding these vaccines.

Chitosan, a biodegradable and biocompatible natural polymer composed of β-(1-4)-linked N-acetyl glucosamine (GlcNAc) and d-glucosamine (GlcN) and derived from crustacean shells, has been widely studied for various biomedical applications, including drug delivery, cartilage repair, wound healing, and tissue engineering, because of its unique physicochemical properties. One of the most promising areas of research is the investigation of the immunomodulatory properties of chitosan, since the biopolymer has been shown to modulate the maturation, activation, cytokine production, and polarization of dendritic cells and macrophages, two key immune cells involved in the initiation and regulation of innate and adaptive immune responses, leading to enhanced immune responses. Several signaling pathways, including the cGAS-STING, STAT-1, and NLRP3 inflammasomes, are involved in chitosan-induced immunomodulation. This review provides a comprehensive overview of the current understanding of the in vitro immunomodulatory effects of chitosan. This information may facilitate the development of chitosan-based therapies and vaccine adjuvants for various immune-related diseases.

This review delves into the potential of antimicrobial peptides (AMPs) as promising candidates for combating arboviruses, focusing on their mechanisms of antiviral activity, challenges, and future directions. AMPs have shown promise in preventing arbovirus attachment to host cells, inducing interferon production, and targeting multiple viral stages, illustrating their multifaceted impact on arbovirus infections. Structural elucidation of AMP-viral complexes is explored to deepen the understanding of molecular determinants governing viral neutralization, paving the way for structure-guided design. Furthermore, this review highlights the potential of AMP-based combination therapies to create synergistic effects that enhance overall treatment outcomes while minimizing the likelihood of resistance development. Challenges such as susceptibility to proteases, toxicity, and scalable production are discussed alongside strategies to address these limitations. Additionally, the expanding applications of AMPs as vaccine adjuvants and antiviral delivery systems are emphasized, underscoring their versatility beyond direct antiviral functions.

cGAS plays an important role in regulating both tumor immune responses and DNA damage repair. Nevertheless, there was little research that comprehensively analyzed the correlation between cGAS and the tumor microenvironment, immune cell infiltration, and DNA damage repair in different cancers. In this study, The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) data were used to analyze the mRNA expression and genomic alterations of cGAS in pan-cancer. The HPA database was used to explore the protein levels of cGAS in normal tissues and cancers. Correlation analysis were performed to explore the role of cGAS in interferon expression, immune cell infiltrations, DNA damage repair, and predictive immune markers. The prognostic value of cGAS was analyzed using survival data from the TCGA, Kaplan-Meier plotter database, and PrognoScan database. Lastly, the role of cGAS in DNA damage repair signaling and interferon signaling was validated in NSCLC cell lines. The results showed that cGAS was widely expressed in human normal tissues and various cancers, and the expression of cGAS was significantly upregulated in almost all of the solid cancers. Genomic analysis indicated that the expression of cGAS was positively correlated with copy number levels, while negatively correlated with the methylation levels of cGAS promoter. In addition, the level of cGAS was positively correlated with type I interferons expression, infiltration levels of most immune cell types, TMB and MSI levels, stromal and immune scores, and DNA damage repair gene sets including nonhomologous end joining and homologous recombination pathway. Survival analysis indicated that cGAS levels were associated with patient prognosis in several cancers. Lastly, in vitro study showed knockdown of cGAS expression inhibits the DNA damage repair signaling pathway and interferon signaling in NSCLC. In conclusions, cGAS is wildly activated in human cancers, which might participate in regulating cancer immunity and DNA damage repair. cGAS could be used as an effective target for cancer treatment and might be a potential predictive immune marker.

Subunit vaccines, significant in next-generation vaccine development, offer precise targeting of immune responses by focusing on specific antigens. However, this precision often comes at the cost of eliciting strong and durable immunity, posing a great challenge to vaccine design. To address this limitation, recent advancements in nanoparticles (NPs) are utilized to enhance antigen delivery efficiency and boost vaccine efficacy. This review examines how the physicochemical properties of NPs influence various stages of the immune response during vaccine delivery and analyzes how different NP types contribute to immune activation and enhance vaccine performance. It then explores the unique characteristics and immune activation mechanisms of these NPs, along with their recent advancements, and highlights their application in subunit vaccines targeting infectious diseases and cancer. Finally, it discusses the challenges in NP-based vaccine development and proposes future directions for innovation in this promising field.

Cancer continues to be a leading factor in mortality and tackling it has been made difficult by the development of immune escape. Furthermore, alternative treatments like surgery, chemotherapy, and radiation have been unsuccessful in eradicating cancer. Despite being effective, they have not succeeded in providing a full cancer treatment and exhibit several negative effects. The field of immunotherapy has been improved by utilizing cancer vaccines, immune checkpoint inhibitors (ICIs), and adoptive cell transfer to enhance immune responses to tumors. Nevertheless, cancer cells need to adapt and become immune to immune reactions, leading to the need for innovative treatment methods. Carbohydrate polymers and their nanoparticles have been beneficial in improving cancer immunotherapy by being customizable to specifically target the immune system. These nanoparticles can change the tumor microenvironment and accelerate immunotherapy by affecting immune cells such as T cells and dendritic cells. Incorporating both chemotherapy and phototherapy into nanoparticles can improve immunotherapy. Furthermore, besides controlling immune reactions, carbohydrate polymer nanoparticles can also be used for theranostic purposes, where they are used to image tumor cells and activate the immune system to eradicate cancer.

In recent years, the exploration of sustainable alternatives in the field of bone tissue engineering has led researchers to focus on marine waste byproducts as a valuable resource. These marine resources, often overlooked remnants of various industries, exhibit a rich composition of hydroxyapatite, collagen, calcium carbonate, and other minerals essential to the complex framework of bone structure. Marine waste by-products can emit gases such as methane and carbon dioxide, highlighting the urgency to repurpose these materials for innovative tissue regeneration solutions, offering a sustainable approach to address environmental challenges while advancing medical science. Using these discarded materials offers a promising pathway for sustainable development in regenerative medicine. This review investigates the distinctive properties of marine waste byproducts, emphasizing their capacity to be recycled effectively to contribute to the rebuilding of bone and cartilage tissue during regeneration processes. We also highlight the compatibility of these resources with biological materials such as platelet-rich plasma (PRP), stem cells, exosomes, and natural bioproducts, as well as nanoparticles (NPs) and polymers. By using the natural potential of these resources, we simultaneously address environmental challenges and promote innovative solutions in skeletal tissue engineering, initiating a new era of environmentally green biomedical research.

H9N2 is the most common avian influenza virus (AIV), which causes significant losses in chickens. Safe and effective vaccines are crucial for the prevention of H9N2 AIVs. Chitosan nanoparticles, as novel adjuvants, enhance vaccine immunity and biocompatibility; however, the impact of particle size on the immunological effects remains underexplored. To solve these problems and to prepare an efficient novel H9N2 vaccine, we constructed four N-2-HACC/CMCS NPs (NHC NPs) of different particle sizes (165.6 ± 12.0 nm, 272.5 ± 7.0 nm, 343.2 ± 8.0 nm, and 443.5 ± 15.0 nm). Subsequent in vivo immunogenicity screening revealed that H9N2 with the 272.5 ± 7.0 nm NHC NPs vaccine group induced higher levels of neutralizing antibodies in the early stage of the immune response, while the 343.2 ± 8.0 nm NHC NPs vaccine group induced higher levels of neutralizing antibodies in the late stages of the immune response. Subsequently, the results of the optimal particle size combination screening revealed that more neutralizing antibodies were induced when the NHC NPs particle size combination of 272.5 ± 7.0 nm:343.2 ± 8.0 nm ratio was 1.5:1. This optimal particle size combination for NP vaccines promoted lymphocyte proliferation, induced higher IgG2a/IgG1 ratios, and promoted the production of cytokines (i.e., IL-2, IL-4, and IFN-γ). Moreover, a mechanistic analysis revealed that the optimal NHC NPs combination triggered the activation of antigen presenting cells via TLR4 and participated in immune responses through the production of NO and TNF-α. Taken together, our study revealed that the optimal combination of NHC NPs may be a promising strategy against influenza viruses.

Chitosan is widely explored in the field of biomedicine due to its abundance and reported properties, including biocompatibility, biodegradability, non-toxicity, mucoadhesion, and anti-microbial activity. Although our understanding of the immune response to chitosan has evolved, confusion remains regarding whether chitosan is a pro- or anti-inflammatory biomaterial. Tackling this knowledge gap is essential for the translation of chitosan-based biomaterials to clinical use. Herein, we provide an overview of the immune responses to chitosan, exploring the roles of endotoxin contamination and physiochemical properties in immunomodulation. Ultimately, this literature review concludes that various physiochemical properties, including molecular weight, degree of deacetylation and polydispersity, endotoxin contamination, and cellular environment, interplay in the complex process of chitosan immunomodulation, which can lead to both pro- and anti-inflammatory effects.

N-dihydrogalactochitosan (GC) is an immune stimulant/adjuvant. Synthesized from chitosan and galactose, GC is a new chemical entity that significantly enhances the immune-stimulating properties of its parental material, chitosan, making it a promising therapeutic agent. When used in combination with antigenic material, GC stimulates innate and adaptive antitumor and antiviral immunities. However, its mechanism has not been fully investigated. Herein we demonstrate that GC drives type I IFN activation in antigen-presenting cells (APCs). More importantly, GC drives alternative STING pathways, leading to inflammatory cell death that enhances dendritic cell (DC) activation. GC-activated DCs trigger a variety of nucleic acid sensing pattern recognition receptors (PRRs) pathways and IL-1β production via the activation of the inflammasome. In vivo, GC induces a potent response of type I IFNs and upregulates genes associated with STING signaling within the tumor microenvironment (TME). Moreover, intratumoral delivery of GC reduces the numbers of M2-like macrophages and increases M1-like macrophages residing within the TME, while subsequently increasing the number of activated DCs. Our findings demonstrate that GC acts as a multimodal immune stimulant via STING to generate a broad type I IFN response. This uniquely broad response holds therapeutic promise in generating enhanced antitumor and antiviral immunities.

Vitamin E (VE) is an essential vitamin liposoluble antioxidant in aquatic animals that is usually lost during feed processing and digestion, whereas nano-chitosan, a polysaccharide, could protect VE. In this study, Nile tilapia (70.85 ± 0.2 g) was fed VE (100 mg/kg dry diet) and a chitosan protected-VE nanoparticle (NPs) with gradual percentages of recommended dose 25%, 50%, 75%, and 100% for 4, 6, and 8 weeks. Growth parameters total weight gain (TG), daily weight gain (DWG), and relative growth rate (RGR) were significantly and positively correlated with VENPs additions. Regardless of the addition level, the feed conversion ratio (FCR) was significantly lower in the VENP groups. Lysozyme, serum antibacterial activity, and oxidative burst activity indicated the superiority of VENPs (VENPs75 and VENPs100) in enhancing the fish's innate immunity compared to bulk VE and the control groups. Fish were experimentally challenged with pathogenic Aeromonas hydrophila; those received dietary showed a low mortality rate (MR%), about 40% compared with 70% in the control with lower re-isolation compared to the control and VE groups. VENPs could provide ascending relative protection level during the period of 4 to 8 weeks; RPL ranged from 33.3 to 42.86% (VENPs100), 16.67-42.86% (VENPs75), 0 to 28.57% (VENPs50), and 0 to 14.29% (VENPs25 and VE), respectively. Finally, this study recommended incorporating VENPs into the Nile tilapia diet at 50, 75, and 100 mg/ kg fish feed. Fish in the VENPs75 and VENPs100 groups were immune boosted, becoming less vulnerable to A. hydrophila infection.

Vaccines are an effective approach to confer immunity against infectious diseases. Modern subunit vaccines offer more precise target and safe protection compared to traditional whole-pathogen vaccines. However, subunit vaccines require adjuvants to stimulate the immune system due to the less immunogenicity. Adjuvants strengthen immunogenicity by enhancing, modulating, and prolonging the immune response. Unfortunately, few adjuvants have sufficient potency and low enough toxicity for clinical use, highlighting the urgent need for new vaccine adjuvants with the characteristics of safety, efficacy, and cost-effectiveness. Notably, some natural polysaccharides have been approved as adjuvants in human vaccines, owing to their intrinsic immunomodulation, low toxicity, and high safety. Natural polysaccharides are mainly derived from plants, bacteria, and yeast. Partly owing to the difficulty of obtaining them, synthetic polysaccharides emerged in clinical trials. The immune mechanisms of both natural and synthetic polysaccharides remain incompletely understood, hindering the rational development of polysaccharide adjuvants. This comprehensive review primarily focused on several promising polysaccharide adjuvants, discussing their recent applications in vaccines and highlighting their immune-modulatory effects. Furthermore, the future perspectives of polysaccharides offer insightful guidance to adjuvant development and application.

The respiratory tract is susceptible to various infections and can be affected by many serious diseases. Vaccination is one of the most promising ways that prevent infectious diseases and treatment of some diseases such as malignancy. Direct delivery of vaccines to the respiratory tract could mimic the natural process of infection and shorten the delivery path, therefore unique mucosal immunity at the first line might be induced and the efficiency of delivery can be high. Despite considerable attempts at the development of respiratory vaccines, the rational formulation design still warrants attention, i.e., how the formulation composition, particle properties, formulation type (liquid or solid), and devices would influence the immune outcome. This article reviews the recent advances in the formulation design and development of respiratory vaccines. The focus is on the state of the art of delivering antigenic compounds through the respiratory tract, overcoming the pulmonary bio-barriers, enhancing delivery efficiencies of respiratory vaccines as well as maintaining the stability of vaccines during storage and use. The choice of devices and the influence of deposition sites on vaccine efficiencies were also reviewed.

Innate immune memory or trained immunity refers to a long-lasting response of the innate immune cells against repeated exposure to the homogenous or heterogenous infectious agent. The trained immunity is induced through epigenetic modification and is characterized by the change of both intracellular immunological signaling and cellular metabolism. Recently, different groups have tried to establish protocols to generate trained innate immune cells. However, the molecular basis of innate memory induction remains poorly understood. Here, we evaluated the impact of water-soluble chitosan on the innate immune memory induction in microglial cells primed with LPS. The trained-immune response was accessed by measuring proinflammatory markers, metabolic change, and epigenetic modification. We showed that the stimulation/restimulation with LPS only caused a robust reduction of iNOS, and proinflammatory cytokines, indicating induced immune tolerance. In contrast, the treatment of chitosan induces long-lasting memory microglial cells accompanied by a high level of iNOS, increased lactate production, induced epigenetic modification, and the upregulation of proinflammatory cytokines upon further exposure to the same stimulus. These findings suggest that chitosan induces microglial-trained immunity by targeting distinct epigenetic and metabolic pathways; therefore, chitosan treatment may provide a novel approach for targeting innate immunity towards a memory-like response in an in vitro model.

The Macrophage-inducible C-type lectin (Mincle) is a pattern-recognition receptor (PRR), which has shown much promise as a molecular target for the development of TH1/TH17-skewing vaccine adjuvants. In 2009, the first non-proteinaceous Mincle ligands, trehalose dimycolate (TDM) and trehalose dibehenate (TDB), were identified. This prompted a search for other Mincle agonists and the exploration of Mincle agonists as vaccine adjuvants for both preventative and therapeutic (anti-cancer) vaccines. In this review, we discuss those classes of Mincle agonists that have been explored for their adjuvant potential. These Mincle agonists have been used as stand-alone adjuvants or in combination with other pathogen-associated molecular patterns (PAMPs) or immunomodulatory agents. We will also highlight recently identified Mincle ligands with hitherto unknown adjuvanticity. Conjugate vaccines that contain covalently linked adjuvants and/or adjuvant-antigen combinations are also presented, as well as the different formulations (e.g., oil-in-water emulsions, liposomes, and particulate delivery systems) that have been used for the codelivery of antigens and adjuvants. Insofar the reader is presented with a thorough review of the potential of Mincle-mediated vaccine adjuvants, including historical context, present-day research and clinical trials, and outstanding research questions, such as the role of ligand presentation and Mincle clustering, which, if better understood, will aid in the development of the much-needed TH1/TH17-skewing vaccine adjuvants.