Programmable metal-nucleic acid biomineralized hydrogel for infected wound healing via mitochondrial regulation

Chronic infected wounds represent a significant clinical challenge due to bacterial infection, dysregulated inflammation, and excessive reactive oxygen species (ROS) that impair tissue repair and are exacerbated by antibiotic resistance. To overcome these limitations, we developed Cu-Tsi@Gel, a programmable biomineralized hydrogel integrating sulfated tetrahedral framework nucleic acids (sTDNs), copper ions (Cu²⁺), and tumor necrosis factor-α (TNF-α) siRNA (siTNF-α) within a photocrosslinkable GelMA matrix. This design integrates organic and inorganic components via thiol-directed biomineralization, enabling three key functions. The Cu²⁺/Cu⁺ redox cycling confers sustained antioxidant activity, restoring mitochondrial redox balance and protecting cells from oxidative damage. Concurrently, siTNF-α silences TNF-α expression in macrophages, thereby reducing pro-inflammatory cytokines including interleukin‑6 (IL‑6) and IL‑1β. Cu-Tsi@Gel disrupts bacteria membranes, kills bacteria (including S. aureus, MRSA and E. coli), and promotes angiogenesis through vascular endothelial growth factor (VEGF) /CD31 upregulation. In infected murine wounds, Cu-Tsi@Gel accelerated closure, enhanced collagen deposition, stimulated neovascularization, and reduced inflammation compared with controls. This multifunctional hydrogel offers a promising strategy for treating infected chronic wounds by concurrently targeting antimicrobial resistance, oxidative stress, and inflammatory pathways. STATEMENT OF SIGNIFICANCE: Conventional biomaterials typically combine therapeutic components in a passive or additive manner. Here, we introduce a programmable biomineralized hydrogel that achieves synergistic integration of copper ions, thiolated DNA nanostructures, and therapeutic siRNA within a unified framework. The central innovation lies in a copper-DNA architecture that confers cell‑discriminative redox behavior: it selectively induces oxidative stress in bacteria while protecting mammalian cells. This structural design enables coordinated antimicrobial activity, gene silencing, and vascularization from a single platform. By demonstrating how nucleic acid scaffolds can orchestrate inorganic bioactivity with precise biological regulation, this work establishes a versatile paradigm for rationally designed multifunctional biomaterials.