Biomaterials are substances that can be injected, implanted, or applied to the surface of tissues in biomedical applications and have the ability to interact with biological systems to initiate therapeutic responses. Biomaterial-based vaccine delivery systems possess robust packaging capabilities, enabling sustained and localized drug release at the target site. Throughout the vaccine delivery process, they can contribute to protecting, stabilizing, and guiding the immunogen while also serving as adjuvants to enhance vaccine efficacy. In this article, we provide a comprehensive review of the contributions of biomaterials to the advancement of vaccine development. We begin by categorizing biomaterial types and properties, detailing their reprocessing strategies, and exploring several common delivery systems, such as polymeric nanoparticles, lipid nanoparticles, hydrogels, and microneedles. Additionally, we investigated how the physicochemical properties and delivery routes of biomaterials influence immune responses. Notably, we delve into the design considerations of biomaterials as vaccine adjuvants, showcasing their application in vaccine development for cancer, acquired immunodeficiency syndrome, influenza, corona virus disease 2019 (COVID-19), tuberculosis, malaria, and hepatitis B. Throughout this review, we highlight successful instances where biomaterials have enhanced vaccine efficacy and discuss the limitations and future directions of biomaterials in vaccine delivery and immunotherapy. This review aims to offer researchers a comprehensive understanding of the application of biomaterials in vaccine development and stimulate further progress in related fields.

Therapeutic cancer vaccines are among the first FDA-approved cancer immunotherapies. Among them, it remains a major challenge to achieve robust lymph-node (LN) accumulation. However, delivering cargo into LN is difficult owing to the unique structure of the lymphatics, and clinical responses have been largely disappointing. Herein, inspired by the Migrated-DCs homing from the periphery to the LNs, an injectable hydrogel-based polypeptide vaccine system is described for enhancing immunostimulatory efficacy, which could form a local niche of vaccine \"hitchhiking\" on DCs. The OVA peptide modified by lipophilic DSPE domains in the hydrogel is spontaneously inserted into the cell membrane to achieve \"antigen anchoring\" on DCs in vivo. Overall, OVA peptide achieves active access LNs through recruiting and \"hitchhiking\" subcutaneous Migrated-DCs. Remarkably, it is demonstrated that the composite hydrogel enhances LNs targeting efficacy by approximately six-fold compared to free OVA peptide. Then, OVA peptide can be removed from the cell surface under a typical acidic microenvironment within the LNs, further share them with LN-resident APCs via the \"One-to-Many\" strategy (One Migrated-DC corresponding to Many LN-resident APCs), thereby activating powerful immune stimulation. Moreover, the hydrogel vaccine exhibits significant tumor growth inhibition in melanoma and inhibits pulmonary metastatic nodule formation.

Tumor vaccines have been considered a promising therapeutic approach for treating cancer in recent years. With the development of sequencing technologies, tumor vaccines based on neoantigens or genomes specifically expressed in tumor cells, mainly in the form of peptides, nucleic acids, and dendritic cells, are beginning to receive widespread attention. Therefore, in this review, we have introduced different forms of neoantigen vaccines and discussed the development of these vaccines in treating cancer. Furthermore, neoantigen vaccines are influenced by factors such as antigen stability, weak immunogenicity, and biosafety in addition to sequencing technology. Hence, the biological nanomaterials, polymeric nanomaterials, inorganic nanomaterials, etc., used as vaccine carriers are principally summarized here, which may contribute to the design of neoantigen vaccines for improved stability and better efficacy.

Therapeutic cancer vaccines offer the greatest advantage of enhancing antigen-specific immunity against tumors, particularly for immunogenic tumors, such as melanoma. However, clinical responses remain unsatisfactory, primarily due to inadequate T cell priming and the development of acquired immune tolerance. A major obstacle lies in the inefficient uptake of antigen by peripheral dendritic cells (DCs) and their migration to lymph nodes for antigen presentation. In this context, the magnetic delivery of antigen-loaded magnetic liposomes (Ag-MLs) to actively target lymph node, is proposed. These magnetic responsive liposomes contain soluble mouse melanoma lysate and iron oxide nanoparticles in the core, along with the immunostimulatory adjuvant CpG-1826 incorporated into the lipid bilayer. When applied through magnetic targeting in the mouse melanoma model, Ag-MLs accumulate significantly in the target lymph nodes. This accumulation results in increased population of active DCs in lymph nodes and cytotoxic T lymphocytes (CTLs) within tumors, correlating with effective tumor growth inhibition. Overall, this study demonstrates the potential of magnetic targeting as an effective strategy for delivering cancer vaccines and activating the immune response, offering a novel platform for cancer immunotherapies.

Hydrogel has been proven to have the ability to deliver antigens continuously to achieve slow vaccine delivery, which makes it a promising candidate for an adjuvant delivery platform. Meanwhile, graphene oxide (GO) has garnered significant attention due to its good biosafety, excellent surface area and easy modification. However, GO exists as weak colloidal particles and poses challenges in self-assembling into a hydrogel structure. Here, we propose an innovative strategy involving self-assembling lentinan-functionalized graphene oxide hydrogel ((LNT-GO Gel) by simply mixing lentinan (LNT)-functionalized GO with polyethylene imide (PEI), which can simultaneously encapsulate antigens, achieve long-lasting release of antigens and generate excellent adjuvant activity. The results indicated that the LNT-GO Gel can control the release of OVA at the injection site and confer targeted delivering capacity to lymph nodes. And the date demonstrates that LNT-GO Gel displays favorable safety and biodegradability in vivo. Moreover, LNT-GO Gel can enhance the activation and maturation of dendritic cells (DCs) in lymph node, induce stronger OVA-specific antibody response, and promote spleen T lymphocyte differentiation, which underscores that LNT-GO Gel has ability to generate stronger antigen-specific humoral and cellular immune responses. Collectively, these results demonstrate the adjuvant potential of the lentinan-functionalized graphene oxide hydrogel (LNT-GO Gel) for subunit vaccine.

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Microneedles are a well-known transdermal or transdermal drug delivery system. Different from intramuscular injection, intravenous injection, etc., the microneedle delivery system provides unique characteristics for immunotherapy administration. Microneedles can deliver immunotherapeutic agents to the epidermis and dermis, where immune cells are abundant, unlike conventional vaccine systems. Furthermore, microneedle devices can be designed to respond to certain endogenous or exogenous stimuli including pH, reactive oxygen species (ROS), enzyme, light, temperature, or mechanical force, thereby allowing controlled release of active compounds in the epidermis and dermis. In this way, multifunctional or stimuli-responsive microneedles for immunotherapy could enhance the efficacy of immune responses to prevent or mitigate disease progression and lessen systemic adverse effects on healthy tissues and organs. Since microneedles are a promising drug delivery system for accurate delivery and controlled drug release, this review focuses on the progress of using reactive microneedles for immunotherapy, especially for tumors. Limitations of current microneedle system are summarized, and the controllable administration and targeting of reactive microneedle systems are examined.

Vaccination is an effective measure to prevent infectious diseases. Protective immunity is induced when the immune system is exposed to a vaccine formulation with appropriate immunogenicity. However, traditional injection vaccination is always accompanied by fear and severe pain. As an emerging vaccine delivery tool, microneedles overcome the problems associated with routine needle vaccination, which can effectively deliver vaccines rich in antigen-presenting cells (APCs) to the epidermis and dermis painlessly, inducing a strong immune response. In addition, microneedles have the advantages of avoiding cold chain storage and have the flexibility of self-operation, which can solve the logistics and delivery obstacles of vaccines, covering the vaccination of the special population more easily and conveniently. Examples include people in rural areas with restricted vaccine storage facilities and medical professionals, elderly and disabled people with limited mobility, infants and young children afraid of pain. Currently, in the late stage of fighting against COVID-19, the main task is to increase the coverage of vaccines, especially for special populations. To address this challenge, microneedle-based vaccines have great potential to increase global vaccination rates and save many lives. This review describes the current progress of microneedles as a vaccine delivery system and its prospects in achieving mass vaccination against SARS-CoV-2.

The delivery of nucleic acid vaccine to stimulate host immune responses against Coronavirus disease 2019 shows promise. However, nucleic acid vaccines have drawbacks, including rapid clearance and poor cellular uptake, that limit their therapeutic potential. Microrobots can be engineered to sustain vaccine release and further control the interactions with immune cells that are vital for robust vaccination. Here, the 3D fabrication of biocompatible and biodegradable microrobots via the two-photon polymerization of gelatin methacryloyl (GelMA) and their proof-of-concept application for DNA vaccine delivery is reported. Programmed degradation and drug release by varying the local exposure dose in 3D laser lithography and further functionalized the GelMA microspheres with polyethyleneimine for DNA vaccine delivery to dendritic cell and primary cells is demonstrated. In mice, the DNA vaccine delivered by functionalized microspheres elicited fast, enhanced, and durable antigen expression, which may lead to prolonged protection. Furthermore, we demonstrate the maneuverability of microrobots by fabricating GelMA microspheres on magnetic skeletons. In conclusion, GelMA microrobots may provide an efficient vaccination strategy by controlling the expression duration of DNA vaccines.

Utilization of the intestinal lymphatic pathway will allow extraordinary gains in lymph and tumors cascade-targeted delivery of oral drugs and awakening the innate/adaptive immunity of the body and the lesion microenvironment, in addition to improving oral bioavailability relative to other means of delivery of oral drugs. Here, inspired by the specific invasion route of intestinal microorganisms, we pioneered an immune-awakening Saccharomyces-inspired mesoporous silicon nanoparticle (yMSN) for the ingenious cascade-targeted delivery of therapeutic cancer vaccines and antitumor drugs to lymph and tumors via the intestinal lymphatic pathway. Encouragingly, yMSN high-loaded tumor-specific antigens (OVA, 11.9%) and anti-tumor drugs (Len, 28.6%) with high stability, namely Len/OVA/yMSN, efficiently co-delivered OVA and Len to their desired target sites. Moreover, yMSN concomitantly awakened the innate antitumor immunity of dendritic cells and macrophages, strengthening vaccine-induced adaptive immune responses and reversing macrophage-associated immunosuppression in the tumor microenvironment. Surprisingly, Len/OVA/yMSN treatment resulted in excellent synergistic antitumor efficacy and long-term antitumor memory in OVA-Hepa1-6-bearing mice. This high-performance nanocarrier provides a novel approach for lesion-targeting delivery of oral drugs accompanied with awakening of the innate/adaptive immunity of the lesion environment, and also represents a novel path for the oral delivery of diverse therapeutic agents targeting other lymph-mediated diseases.