Topical framework nucleic acid transdermal delivery system for reprogramming cutaneous dendritic cells to maintain graft immune homeostasis

Immune rejection is a major challenge for the long-term survival of allogeneic skin grafts. Current immunosuppressive therapies are usually administered systemically to mitigate rejection; however, they have substantial side effects. Therefore, here, a localized immunomodulatory strategy based on tetrahedral framework nucleic acids (tFNAs) is proposed to improve the survival of allogeneic skin grafts. A mircoRNA (miR-23b) and a dendritic cell-targeting aptamer is conjugated to tFNAs to create a complex (termed TR), which is embedded in a four-armed PEG hydrogel (MixPEG) matrix to form MixPEG-TR. TR targets dendritic cells (DCs) in the skin to induce tolerogenic DCs by leveraging the transdermal delivery capability of tFNAs and the sustained release provided by the hydrogel, thereby establishing persistent local immune tolerance. The local application of this formulation reduces inflammatory cell infiltration, promotes uniform dermal collagen deposition, and markedly prolongs graft survival in a mouse allogeneic skin graft model. These findings highlight a transdermal, DC-targeted nucleic acid delivery strategy capable of enhancing local immune tolerance and alleviating inflammatory responses, thereby potentially maintaining graft-associated immune homeostasis and providing a safer, site-specific platform for immunomodulation in skin transplantation and other cutaneous immune-mediated conditions. Topical Framework Nucleic Acid Transdermal Delivery System for Reprogramming Cutaneous Dendritic Cells to Maintain Graft Immune Homeostasis. • Developed a topical, transdermal DC-targeting nucleic-acid delivery system by embedding an aptamer/miR-23b–loaded tFNA (TR) into a four-arm PEG hydrogel (MixPEG) for local retention and sustained release. • TR suppressed LPS-induced DC maturation in vitro, reducing co-stimulatory markers and inflammatory signaling while increasing IL-10, consistent with a tolerogenic DC phenotype. • In a mouse allogeneic skin graft model, local MixPEG-TR treatment reduced rejection-associated inflammation and prolonged graft survival. • MixPEG-TR shifted systemic immune responses toward tolerance, with increased Treg and reduced CD8 + effector T cells. • Metabolomics suggested tolerance was associated with reprogrammed lipid- and arginine-related metabolic pathways.