Dissolving microneedle array size influences physical adjuvanticity for dose-sparing vaccination

Dissolving microneedles (DMNs) are an emerging biomaterial platform for transdermal vaccination, enabling precise antigen delivery into antigen-presenting cell-rich skin layers. Here, we identify a previously underappreciated size dependent immunomodulatory biomaterial function of DMNs: their ability to act as physical adjuvants through controlled tissue micro-injury. Microneedle insertion generates spatially distributed and transient skin micro-injury that induces the release of damage-associated molecular patterns, prominently high-mobility group box 1 (HMGB-1), thereby establishing a localized inflammatory field that bridges mechanical input to immune activation. Importantly, the magnitude of this response is quantitatively governed by microneedle array size, revealing device architecture as a tunable design parameter for modulating biological outcomes. Array size-dependent micro-injury promoted dendritic cell activation and lymphatic trafficking, resulting in enhanced humoral responses, including elevated antigen-specific IgG titers and increased plasma cell frequencies, even in the absence of exogenous adjuvants. Despite robust innate activation, DMN-induced inflammation was localized and fully resolved within one week, demonstrating favorable tissue compatibility. Collectively, these findings establish microneedle array design as a controllable biomaterial-based strategy to program physical adjuvanticity, enabling safe, adjuvant-free, and dose-sparing vaccination.