Coordination of Functional Oligonucleotides Yields a Versatile Nanocomposite Microneedle Patch to Facilitate Local Wound Microenvironment Remodeling via Systemic Hyperglycemia Regulation

Abstract Hyperglycemia exacerbates bacterial infections, disrupts angiogenesis, and perpetuates chronic inflammation in the wound. Therefore, the effective management of diabetic wounds necessitates a synergistic approach that integrates local wound microenvironment remodeling with systemic hyperglycemia regulation. Herein, an unprecedented hierarchical cobalt pyrophosphate/DNA (Co 2 PPi/DNA) nanocomposite is reported for this purpose. Unlike the stereotypical assembly of either enzymatically polymerized ultralong nucleic acids with Mg 2 PPi nanosheets at low assembly ratios or commercial homo‐oligonucleotides devoid of biofunctionalities in the presence of metal ions, this study represents the first demonstration on coordination‐driven high‐efficiency co‐assembly of biofunctional hetero‐oligonucleotides and non‐Mg 2 PPi nanosheets, specifically glucagon receptor (GCGR) aptamer and Co 2 PPi nanosheets. To improve the bioavailability of nanocomposites, a dissolvable microneedle patch is applied for their wound delivery. Thereafter, nanocomposites dissociate in the wound for sustained release of Co 2+ ions and GCGR aptamer, from which Co 2+ ions eliminate colonized bacteria and promote angiogenesis through stabilizing HIF‐1α, meanwhile, aptamer after circulating to liver reduces blood glucose levels by binding to hepatocyte GCGR. Importantly, this hypoglycemic effect promotes antibacterial and pro‐angiogenic efficacy and alleviates the inflammatory responses. This work highlights significant advancements in the coordination of biofunctional hetero‐oligonucleotides into a versatile nanocomposite architecture to remodel local pathological microenvironment facilitated by systemic factor regulation.