A dual-targeted oligonucleotide delivery hydrogel for diabetic wound healing: Regulating macrophage-endothelial crosstalk and ferroptosis.

The diabetic microenvironment induces excessive M1 macrophage infiltration and severe oxidative stress, triggering endothelial cell ferroptosis and delaying wound healing. However, effective strategies for precise immune modulation and intracellular oligonucleotide delivery remain limited due to lysosomal degradation. Here, we developed a semi-i-motif-modified tetrahedral framework nucleic acid platform (IT) that co-delivers miR-125b-5p and an anti-HMGB1 aptamer (RHIT) to regulate macrophage-mediated inflammation. Mechanistically, RHIT leverages the proton sponge effect for lysosomal escape and specifically recognizes macrophages. It synergistically activates the Nrf2 axis and suppresses the HMGB1/MAPK signaling pathway. This intervention promotes macrophage M2 polarization, attenuates inflammation, and protects endothelial cells from ferroptosis through paracrine signaling. To achieve sustained delivery and stable tissue adhesion, we integrated RHIT into an adhesive composite GelMA/4-PEG-SS-based hydrogel (GS), constructing the RHIT@GS system. The RHIT@GS hydrogel significantly accelerated wound repair, enhanced M2 macrophage polarization, and promoted angiogenesis in a diabetic model. Our findings demonstrate that this integrated system precisely remodels the pathological immune microenvironment, establishing a promising oligonucleotide-based therapeutic strategy for clinical diabetic wound regeneration.