Can Microneedle-Nanocarrier Platforms Deliver True Tolerogenic Immunotherapy for Psoriasis?

Abstract

Psoriasis is a chronic, relapsing skin disease driven by failed immune tolerance toward self-antigens and sustained IL-23/IL-17 signaling. Systemic drugs and biologics control disease in many patients, yet they do not restore lasting tolerance, and most patients relapse after treatment withdrawal. Tolerogenic vaccines aim to re-educate the cutaneous immune system: when administered under non-inflammatory conditions, they push antigen-presenting cells toward tolerogenic dendritic cells (tDCs) and regulatory T cells (Tregs) instead of pathogenic effectors. Because the hyperkeratotic stratum corneum of psoriatic plaques blocks macromolecular vaccines, microneedle (MN) arrays can deposit nanocarriers directly into the dermal-epidermal junction. The narrative review asks whether MN-delivered tolerogenic nanovaccines can advance psoriasis therapy beyond broad immunosuppression. We first define tolerogenic vaccination and explicitly distinguish antigen-specific tolerogenic vaccines, antigen-independent immune-reprogramming nanocarriers, and conventional local drug delivery, then survey MN engineering and nanocarrier architectures, the immunomodulatory pathways involved, and translational barriers spanning manufacturing, safety, and regulation. Because most evidence is preclinical, the level of evidence is reported for each platform, and the unresolved autoantigen problem, the limitations of imiquimod-based models, and the need for human-relevant validation are emphasized.