Layer-Specific Dermal and Subcutaneous Delivery via Modular LNP-Hydrogel-Integrated Threaded Microneedles.

Skin diseases exhibit hierarchical pathological remodeling across the epidermis, dermis, and subcutaneous tissue. However, current therapies lack precise and controllable layer-specific intervention. Here, we present a threaded microneedle-mRNA platform enabling stratified, targeted delivery. Guided by spatial transcriptomics and clinical validation, we identified layer-specific targets in skin fibrosis. Optimized lipid nanoparticles (LNPs) were integrated into a microneedle design featuring a fast-releasing superficial hydrogel that delivers a SIRT1 agonist to mitigate dermal fibroblast senescence, and helical grooves that directionally deposit PGC1α mRNA-LNPs into subcutaneous adipose during rotational insertion for in situ expression and reversal of adipocyte fibrotic phenotypes. In bleomycin-induced murine fibrosis, the system reduced dermal senescence and ECM deposition, restored subcutaneous adipose architecture, and attenuated overall fibrosis. This layer-specific microneedle-mRNA strategy offers a precise therapeutic pathway for complex skin diseases.