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Conventional treatments for tumors were frequently accompanied by drawbacks and side effects. It might be useful to use the revolutionary microneedle technology which combines photothermal therapy with tumor immunotherapy. In this study, we created a microneedle drug delivery system with mercapto-modified gold nanorods and immune checkpoint blocker anti-PD-1 polypeptide. With good mechanical strength, the microneedle system can efficiently penetrate the skin and deliver drugs. When inserted into human skin, anti-PD-1 peptides and gold nanorods can be released, boosting the capacity of cytotoxic T lymphocytes to destroy tumor cells. Additionally, the elimination of the tumor is aided by the production of heat while being exposed to near-infrared light. This microneedle drug delivery system can enhance the immunological reaction and prolong the survival time of mice. Moreover, it has been demonstrated that the system has mild toxic and side effects on normal tissues and can effectively inhibit the growth of tumors, indicating a bright prospect for the treatment of cancers.

Avian influenza H7N9 virus has first emerged in 2013 and since then has spread in China in five seasonal waves. In humans, influenza H7N9 virus infection is associated with a high fatality rate; thus, an effective vaccine for this virus is needed. In the present study, we evaluated the usefulness of dissolving microneedles (MNs) loaded with influenza H7N9 vaccine in terms of the dissolution time, insertion capacity, insertion depth, and structural integrity of H7N9 virus in vitro. Our in vitro results showed MNs dissolved within 6 mins. The depth of skin penetration was 270 µm. After coating with a matrix material solution, the H7N9 proteins were agglomerated. We detected the H7N9 delivery time and humoral immune response in vivo. In a mouse model, the antigen retention time was longer for MNs than for intramuscular (IM) injection. The humoral response showed that similar to IM administration, MN administration increased the levels of functional and systematic antibodies and protection against the live influenza A/Anhui/01/2013 virus (Ah01/H7N9). The protection level was determined by the analysis of pathological sections of infected lungs. MN and IM administration yielded results superior to those in the control group. Taken together, these findings demonstrate that the use of dissolving MNs to deliver influenza H7N9 vaccines is a promising immunization approach.

Staphylococcal enterotoxin B (SEB) produced by the Staphylococcus aureus bacteriumis most commonly associated with food poisoning and is known to also cause toxic shock syndrome. Currently, no approved vaccine or specific drug is available to treat SEB intoxication. In this study, we fabricated dissolving microneedles (MNs) loaded with recombinant SEB (rSEB) protein, and evaluated its characteristics, including dissolution profile, protein particle size, insertion depth, antigen retention time in vivo, and skin irritation. Our results showed that rSEB protein-loaded dissolving MNs made of chondroitin sulfate (2%) and trehalose (0.8%) could easily penetrate into the mouse skin within 5 min. The rSEB particle size was unchanged before and after MN fabrication. The skin penetration depth of the MNs was 260 µm. Moreover, the MNs also significantly extended the antigen retention time in vivo. rSEB protein-loaded dissolving MNs also triggered slight erythema at the beginning of administration, but this erythema disappeared within a few hours. More importantly, we investigated the immunogenicity and protective efficacy of rSEB protein-loaded dissolving MNs. Challenge studies in mice revealed that mice in full-dose MN group had a high level of SEB specific antibody response thatprovided100% protection against a lethal SEB toxin challenge. However, there was only 60% protection observed in mice that were in the half-dose MN (dose sparing) group. We also determined the pathological alterations in the tissues of the immunized mice. Taken together, these dissolving MNs may present a promising transcutaneous immunization strategy for treating SEB intoxication.

Transcutaneous immunization (TCI) via needle-free and non-invasive drug delivery systems is a promising approach for overcoming the current limitations of conventional parenteral vaccination methods. The targeted access to professional antigen-presenting cell (APC) populations within the skin, such as Langerhans cells (LCs), various dermal dendritic cells (dDCs), macrophages, and others makes the skin an ideal vaccination site to specifically shape immune responses as required. The stratum corneum (SC) of the skin is the main penetration barrier that needs to be overcome by the vaccine components in a coordinated way to achieve optimal access to dermal APC populations that induce priming of T-cell or B-cell responses for protective immunity. While there are numerous approaches to penetrating the SC, such as electroporation, sono- or iontophoresis, barrier and ablative methods, jet and powder injectors, and microneedle-mediated transport, we will focus this review on the recent progress made in particle-based systems for TCI. This particular approach delivers vaccine antigens together with adjuvants to perifollicular APCs by diffusion and deposition in hair follicles. Different delivery systems including nanoparticles and lipid-based systems, for example, solid nano-emulsions, and their impact on immune cells and generation of a memory effect are discussed. Moreover, challenges for TCI are addressed, including timely and targeted delivery of antigens and adjuvants to APCs within the skin as well as a deeper understanding of the ill-defined mechanisms leading to the induction of effective memory responses.

Tumor development and progression is shaped by the tumor microenvironment (TME), a heterogeneous assembly of infiltrating and resident host cells, their secreted mediators and intercellular matrix. In this context, tumors are infiltrated by various immune cells with either pro-tumoral or anti-tumoral functions. Recently, we published our non-invasive immunization platform DIVA suitable as a therapeutic vaccination method, further optimized by repeated application (DIVA 2 ). In our present work, we revealed the therapeutic effect of DIVA 2 in an MC38 tumor model and specifically focused on the mechanisms induced in the TME after immunization. DIVA 2 resulted in transient tumor control followed by an immune evasion phase within three weeks after the initial tumor inoculation. High-dimensional flow cytometry analysis and single-cell mRNA-sequencing of tumor-infiltrating leukocytes revealed cytotoxic CD8 + T cells as key players in the immune control phase. In the immune evasion phase, inflammatory CCR2 + PDL-1 + monocytes with immunosuppressive properties were recruited into the tumor leading to suppression of DIVA 2 -induced tumor-reactive T cells. Depletion of CCR2 + cells with specific antibodies resulted in prolonged survival revealing CCR2 + monocytes as important for tumor immune escape in the TME. In summary, the present work provides a platform for generating a strong antigen-specific primary and memory T cell immune response using the optimized transcutaneous immunization method DIVA 2 . This enables protection against tumors by therapeutic immune control of solid tumors and highlights the immunosuppressive influence of tumor infiltrating CCR2 + monocytes that need to be inactivated in addition for successful cancer immunotherapy.

► We investigated transfollicular vaccination via intact skin using nanoparticles(NP). ► Polymeric NP from PLGA+- chitosan were loaded with ovalbumin (OVA). ► OVA/NP stimulated proliferation of CD4+ &/or CD8+ T-cells more than OVA/solution. ► NP improved (×2–3) follicular delivery of OVA on pig ears compared to OVA/solution. ► Consequently using OVA/NP one may reduce the dose compared to OVA/solution. Transfollicular vaccination aims to reach the peri-follicular antigen presenting cells without impairing the stratum corneum (SC) barrier. This would be an optimal vaccination strategy under critical hygienic conditions. Nanoparticles (NPs) are the ideal vehicles for transfollicular delivery of vaccines as they are able to (i) penetrate deeper into the hair follicles than molecules in solution, (ii) can help to stabilize protein based antigen and (iii) improve and modulate the immune response. This study investigates the potential of transfollicular delivery of polymeric NPs using ovalbumin (OVA) as a model antigen. NPs were prepared by a double emulsion method from pharmaceutically well characterized biocompatible and biodegradable polymers poly(lactide-co-glycolide) (PLGA) or chitosan-coated PLGA (Chit-PLGA) using polyvinyl alcohol as stabilizer. The NP formulations are available as freeze dried product which can be re-constituted with water or cell culture medium before use to yield any desired OVA/NP concentration. OVA was protected from cleavage or aggregation inside the NPs and retained its biological activity to 74% (PLGA) and 64% (Chit-PLGA). Thus, when applying a typical dose of 8.5μl/cm2 NP formulation (50mg NPs/ml, 54.3±0.047 and 66.5±0.044μg OVA/mg NPs for PLGA and Chit-PLGA NPs, respectively) an effective dose of 17μg/cm2 (PLGA) or 18μg/cm2 (Chit-PLGA) of active OVA is administered. In a cell culture assay encapsulated OVA stimulated the proliferation of CD4+ (PLGA and Chit-PLGA) and CD8+ T-cells (only Chit-PLGA) to a larger extent than OVA in solution. An adoptive transfer experiment demonstrated that the model antigen OVA can be delivered via the transfollicular route. This preliminary experiment is a proof of concept that by this transfollicular immunization approach it is possible to deliver antigens, thereby stimulating antigen-specific T cells. Both NP formulations improved the delivery efficiency of OVA into the hair follicles on excised pig ears by a factor of 2–3 compared to OVA solution. This delivery efficiency could further be increased by increasing the number of NPs applied per skin area by a factor of ≈2–2.4. Consequently formulation of OVA into PLGA and Chit-PLGA NPs may offer to reduce the dose which needs to be applied for transfollicular immunization.

Recent advances in biotechnology have fundamentally reshaped the landscape of vaccine development, offering innovative strategies to improve immunogenicity, safety and accessibility. This review explores the cutting-edge platforms—including mRNA, DNA, virus-like particles, viral and bacterial vectors, and bacteriophage-based vaccines—that are redefining how vaccine antigens are delivered to the immune system. We also discuss alternative delivery methods, such as transcutaneous and mucosal immunization, which have the potential to improve vaccine acceptance and distribution, as well as next-generation adjuvants targeting innate immune receptors aiming to further enhance vaccine efficacy, especially in vulnerable populations. By synthesizing these innovations, this review highlights how biotechnology is enabling the design of safer, more efficient, and more adaptable vaccines to address both existing and emerging infectious diseases.

We are interested in promoting the development of transcutaneous immunization using microneedle technology and attempting to apply an adjuvant with transcutaneous immunization to improve the efficacy and reduce the amount of antigen and number of administrations needed. In this study, we collected basic information to help elucidate the mechanism responsible for the transcutaneous adjuvant activity of imiquimod (IMQ), which is a ligand of toll-like receptor (TLR) 7. In mouse groups administered ovalbumin (OVA), the OVA-specific IgG antibody titer of the IMQ-adjuvanted group was higher than that of the group administered OVA alone. No immune response bias due to transcutaneous IMQ administration was observed in terms of IgG1 (T helper cell [Th]2-type IgG subclass) and IgG2c (Th1-type IgG subclass) antibody titers. After the initial immunization, the IMQ-adjuvanted group showed increased migration of Langerhans cells to draining lymph nodes (dLNs) and active proliferation of OVA-specific CD4+ T cells. Transcutaneously administered IMQ did not affect the direction of CD4+ T cell differentiation, while promoted B cell activation and germinal center (GC) B cell differentiation. Immune staining revealed greater GC formation in the dLNs with the IMQ-adjuvanted group than in the OVA-alone group. In the secondary immune response, effector T cells increased in the dLNs and spleen, and effector memory T cells also increased in the spleen in the IMQ-adjuvanted group. In addition, our results suggested that the administration of IMQ enhanced B cell differentiation into plasma cells and GC B cells in the dLNs and spleen. In this study, we partially clarified the mechanism underlying the adjuvant activity of transcutaneously administered IMQ, which is required for the practical application of transcutaneous immunization with IMQ.