Adaptable Covalent Organic Framework-Hydrogel Microneedles for Glucose-Responsive Isoliquiritigenin Delivery in Diabetic Wound Therapy.

Effective management of diabetic wound healing remains a significant clinical challenge, primarily due to the persistent inflammatory microenvironment and the lack of effective sustained drug delivery strategies that promote tissue regeneration. This pathological stagnation is increasingly attributed to the overactivation of Z-DNA binding protein 1 (ZBP1), a pivotal innate immune sensor that triggers pro-inflammatory cascades under hyperglycemic conditions. In this study, we developed an adaptive covalent organic framework-hydrogel microneedle (ISL@bCOF-MNs) for glucose-responsive delivery of isoliquiritigenin (ISL). The system utilizes boron-oxygen bonds to conjugate the small-molecule drug ISL with a covalent organic framework, which is integrated into microneedles composed of a biomimetic interfacial-bonding nanocomposite hydrogel, which exhibits high transdermal permeability for deep dermal drug delivery. In vitro experiments show that the ISL@bCOF nanodrug dynamically releases ISL in response to hyperglycemic conditions, thereby suppressing inflammation and scavenging reactive oxygen species via targeting of ZBP1. In vivo studies confirm that the microneedle-based transdermal delivery system effectively regulates inflammation and promotes full-thickness wound healing in diabetic mouse models. This work elucidates a potential mechanism by which ISL targets ZBP1 to correct the inflammatory microenvironment and enhance collagen tissue regeneration with advanced biomaterials, offering a promising translational strategy for the clinical management of diabetic wounds.