Microneedle-mediated delivery of DNA and mRNA therapeutics for cancer immunotherapy: advances, design strategies and translational challenges
Nucleic acid therapeutics, particularly DNA and messenger RNA (mRNA), provide programmable platforms for cancer vaccination, local expression of immunomodulatory proteins, and gene regulation. Their therapeutic performance, however, is strongly constrained by extracellular degradation, route-dependent biodistribution, inefficient cellular uptake, and limited delivery to antigen-presenting cells. Microneedle (MN) systems offer a minimally invasive means of depositing nucleic acids in the epidermis and dermis, where immune cells and lymphatic networks can support local antigen presentation and immune priming. This review critically examines MN-mediated DNA and mRNA delivery for cancer immunotherapy. We first compare the biological requirements and delivery barriers of DNA and mRNA, and then relate these requirements to MN architecture, material selection, mechanical performance, cargomatrix interactions, and release behavior. Representative DNA vaccine, gene-editing, mRNA vaccine, and combination-therapy platforms are discussed with emphasis on what each design solves and which limitations remain. Particular attention is given to delivered-dose variability, intracellular transfection, cargo stability during fabrication and storage, manufacturing consistency, safety after repeated application, and the restricted applicability of MNs to skin and accessible lesions. Rather than treating MNs as a universal replacement for systemic delivery, we position them as a route-specific platform whose clinical value will depend on rational cargodevice matching, standardized potency testing, and validation in translational models.