Framework nucleic acid-based hydrogel for sequential immune regulation and endogenous TGF-β1 capture in wound healing

Wound healing is a highly coordinated process that requires timely resolution of inflammation in the early phase and localized activation of regenerative signals during tissue remodeling. Disruption of this sequential regulation often leads to impaired epithelial regeneration and fibrotic remodeling. Transforming growth factor-β1 (TGF-β1) plays a pivotal role in fibroblast activation and extracellular matrix (ECM) synthesis, yet exogenous delivery is limited by instability, off-target effects and fibrotic scarring risk. To address these challenges, we developed a sequential immune-regenerative strategy, in which early anti-inflammatory modulation is followed by localized enrichment of endogenous regenerative cues. β-peptides with high binding affinity to TGF-β1 were trivalently presented on a tetrahedral framework nucleic acid (tFNA) to enable efficient cytokine capture (over 90 % efficiency), while curcumin was incorporated to provide early-phase immunoregulation by suppressing NF-κB signaling, thereby creating a permissive environment for subsequent remodeling. These dual functions were combined in a β3Tc nanostructure, which was subsequently incorporated into a hyaluronic acid methacryloyl (HAMA) scaffold to form a composite hydrogel (HA-β3Tc). The hydrogel demonstrated excellent physicochemical properties, biocompatibility, and bioactivity. In a full-thickness wound model, HA-β3Tc accelerated wound closure, enhanced fibroblast differentiation, and mitigated scar formation. Collectively, this study presents a synergistic immune-regenerative hydrogel platform that combines sequential early anti-inflammation with late-phase spatial TGF-β1 capture, offering a promising strategy for effective and safe tissue repair.