Biodegradable and Antioxidant DNA Hydrogel as a Cytokine Delivery System for Diabetic Wound Healing

Abstract

Impaired diabetic wound healing is associated with the persistence of chronic inflammation and excessive oxidative stress, which has become one of the most serious clinical challenges. Wound dressings with anti-inflammatory and reactive oxygen species (ROS)-scavenging properties are desirable for diabetic wound treatment. In this study, a shape-adaptable, biodegradable, biocompatible, antioxidant, and immunomodulatory interleukin-33 (IL-33)-cytogel is developed by encapsulating IL-33 into physically cross-linked DNA hydrogels and used as wound dressings to promote diabetic wound healing. The porous microstructures and biodegradable properties of the IL-33-cytogel ensure the local sustained-release of IL-33 in the wound area, where the sustained-release of IL-33 is maintained for at least 7 days. IL-33-cytogel can induce local accumulation of group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs), as well as M1-to-M2 transition at the wound sites. Additionally, the antioxidant and biocompatible characteristics of DNA hydrogels promote the scavenging of intracellular ROS without affecting cell viability. As a result, local inflammation in the diabetic wound area is resolved upon IL-33-cytogel treatment, which is accompanied by improved granulation tissue regeneration and accelerated wound closure. This study demonstrates a promising strategy in tissue engineering and regenerative medicine by incorporating DNA hydrogels and cytokine immunotherapy for promoting diabetic wound healing.

DNA-Based Hydrogels with Multidrug Sequential Release for Promoting Diabetic Wound Regeneration

“…Under diabetic conditions, immune cells can generate excessive ROS, which impedes wound healing. It has been reported that scavenging excess ROS promotes the regeneration of DWs. , DNA molecules are sensitive to a variety of ROS radicals and possess scavenging capabilities. , To verify this, we used methylene blue (MB) as a hydroxyl radical (•OH) indicator to test the ROS-scavenging activity of DNA. Hydroxyl radicals were generated by the Fenton reaction and then incubated with the Y monomer, AgNCs-Y, and the L monomer for 30 min each.…”

“…(2) IL-10, one of the most potent immune modulators, activates the transition of macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotype, − which is encapsulated in Agilegel’s pores and plays an anti-inflammatory role. (3) VEGF- α is covalently conjugated to the L DNA monomer through the strong interaction of biotin–streptavidin (SA), which is used to improve vascular development and promote angiogenesis. , In addition, DNA structures themselves are sensitive to various ROS and serve as effective ROS scavengers …”

“…On days 9 and 10, nonfasting blood glucose (NFBG) was measured and mice with NFBG above 16.7 mM were used to induce a diabetic wound model. The 0.8 cm full-thickness skin wound model was made as previously described . IL-10 and VEGF- α were labeled with Alexa488 and Alexa647 respectively.…”

“…It has been reported that scavenging excess ROS promotes the regeneration of DWs. 6,27 DNA molecules are sensitive to a variety of ROS radicals and possess scavenging capabilities. 43,44 To verify this, we used methylene blue (MB) as a hydroxyl radical To elucidate the mechanism of accelerated DW repair, we comprehensively evaluated the effects of Agilegel on biological and molecular events in four sequential phases of the wound healing process.…”

“…DNA hydrogels, as hierarchical self-assembling biological materials, not only possess common features shared by other hydrogels, but also exhibit designable microstructures and tunable macroscopic mechanical, chemical, and biological properties. − With their modifiability, biodegradability, and biocompatibility, DNA hydrogels serve as excellent carriers for the localized release of complex drugs. , They have found extensive applications in the treatment of various conditions, including spinal cord injuries, cancer, , arthritis, , alveolar bone, and wound healing . Hierarchically structured DNA-based hydrogels enable the utilization of covalent modifications on the primary structure (phosphate backbone) or noncovalent interactions on the secondary structure (base pairs) for drug delivery.…”