Intradermal immunoengineering with mRNA

Intradermal (ID) delivery of mRNA therapeutics offers compelling advantages over intravenous administration, including minimally invasive self-administration, distinctive depot pharmacokinetics with dual lymphatic and vascular drainage, and direct access to the skin's dense immune cell network. While ID nucleic acid delivery has achieved clinical validation in inflammatory contexts such as vaccines and polynucleotide-based tissue regeneration, expansion into non-inflammatory applications such as protein replacement therapy, tolerogenic vaccines, and local antibody production is constrained by poorly understood physical and immunological barriers. This review examines the physicochemical challenges of transfecting dermal cells, including engineering nanoparticle interactions with the lymphovascular network, collagen matrix, and glycosaminoglycans. We then address the immunological landscape of the dermis, discussing cell-type-specific innate sensing by macrophages, dendritic cell subsets, and fibroblasts, and how nanomaterial chemistry shapes these responses. We propose that progress in ID immunoengineering requires mechanistic investigation of the nanomaterial-biological interface and innate immunogenicity resulting from mRNA delivery in human skin models. Strategies that selectively engage the innate immune system will transform the dermis from a barrier into an accessible interface for nucleic acid medicine.