Microneedle-Based Oral Mucosal Vaccines: Mechanisms, Challenges, and Emerging Strategies

Oral mucosal vaccination is a minimally invasive and highly acceptable strategy that can trigger both local and systemic immunity. However, its progress toward clinical use is hindered by salivary washout, the multilayered epithelium, and a tolerance-prone immune environment. Microneedles offer a promising way to overcome these barriers. They deliver antigens beneath the oral surface, place them directly in immune-responsive tissues, and can remain operational in the dynamic, enzyme-rich oral cavity. Recent research shows that microneedles enable precise antigen deposition, stabilize fragile vaccine components, and provide controllable release patterns. Studies using both model antigens and clinically relevant targets suggest that oral microneedle vaccination can induce systemic IgG, mucosal sIgA, and tissue-resident cellular responses. Distal mucosal immune responses have also been observed. These distal responses are consistent with the common mucosal immune system (CMIS), although direct evidence of CMIS-dependent lymphocyte trafficking remains limited. The co-delivery of immunostimulatory materials, adjuvants, or nanoparticle carriers further enhances antigen presentation and helps counteract oral immune tolerance. Despite these advances, several challenges remain. These include clarifying the early immune events in oral tissues, identifying adjuvants suited to the oral environment, and ensuring safety, stability, and user acceptability for clinical translation. Overall, current evidence positions microneedles as a versatile and promising platform for mucosal vaccination. Continued integration of oral immunology with formulation and microneedle design will be essential for moving these systems toward real-world application.