Beyond Needles: Immunomodulatory Hydrogel-Guided Vaccine Delivery Systems

Abstract

Vaccines are critical for combating infectious diseases, saving millions of lives worldwide each year. Effective immunization requires precise vaccine delivery to ensure proper antigen transport and robust immune activation. Traditional vaccine delivery systems, however, face significant challenges, including low immunogenicity and undesirable inflammatory reactions, limiting their efficiency. Encapsulating or binding vaccines within biomaterials has emerged as a promising strategy to overcome these limitations. Among biomaterials, hydrogels have gained considerable attention for their biocompatibility, ability to interact with biological systems, and potential to modulate immune responses. Hydrogels offer a materials science-driven approach for targeted vaccine delivery, addressing the shortcomings of conventional methods while enhancing vaccine efficacy. This review examines the potential of hydrogel-based systems to improve immunogenicity and explores their dual role as immunomodulatory adjuvants. Innovative delivery methods, such as microneedles, patches, and inhalable systems, are discussed as minimally invasive alternatives to traditional administration routes. Additionally, this review addresses critical challenges, including safety, scalability, and regulatory considerations, offering insights into hydrogel-guided strategies for eliciting targeted immune responses and advancing global immunization efforts.

Keywords: adjuvants; biomaterials; hydrogels; immunogenicity; immunomodulation; vaccine delivery.

Figure 3

Overview of respiratory mucosal immune components: Waldeyer’s ring (green), lymph nodes (blue) for systemic IgG responses, and ectopic tissues (red) like NALT and BALT for IgA production. (A) Dimeric IgA production in mucosal sites (BALT and NALT) facilitates immune exclusion by expelling antigens and involving pIgR-dependent secretory IgM and IgD (B). Reproduced with permission from Heida et al., 2022 [142].

Figure 1

Adjuvants mediate their effects through mechanisms such as PRR activation, inflammasome-induced secretion of IL-1β and IL-18, and modulation of MHC antigen presentation. Some adjuvants may employ multiple pathways, including enhancing antigen uptake, PRR signaling, and immune cell recruitment. Created with BioRender.com, https://BioRender.com/m49n412 (accessed on 23 December 2024).

Figure 2

Illustration of immune cell dynamics upon hydrogel implantation, highlighting the recruitment of neutrophils during the first 48 h, followed by monocyte infiltration and differentiation into macrophages. Macrophage polarization into M1 (pro-inflammatory) or M2 (anti-inflammatory and reparative) phenotypes regulates inflammation and potential immunomodulation. Created with BioRender.com, https://BioRender.com/i53p251 (accessed on 23 December 2024).

Figure 4

Preparation and application of double-layered MNP: (A) nano-vaccine with HAP and melanoma peptides, (B) mold-cast double-layered MNP, and (C) dual-function MNP for anti-tumor and regenerative melanoma treatment. Reproduced with permission from Chen et al. (2024) [149].