Impaired wound healing is a growing global concern driven by aging populations and the increasing prevalence of chronic conditions, such as diabetes and obesity. Infection is a major factor that delays wound healing, which can lead to sepsis and multiorgan failure, and even cause death in severe cases1, 2. Currently, antimicrobials such as antibiotics are used to treat infected wounds, however, the dead bacteria accumulating at the site of infection could induce undesirable tissue inflammation3, 4. The dead bacteria can release massive amounts of toxins (Lipopolysaccharide(LPS) in Gram-negative bacteria) and ( Peptidoglycan (PGN) in Gram-positive bacteria) that can activate immune cells to induce excessive inflammation and toxicity, leading to chronic and impaired wound healing5-8 (Figure 1). Therefore, developing strategies to simultaneously inhibit the survival of live bacteria and dead bacteria-induced excessive inflammation to heal infected wounds is urgently needed.
LPS/PGN is a structural component of the bacteria cell wall, which maintains the integrity of the bacteria and protects the bacteria against antibacterial treatments. On the other hand, LPS/PGN is the main functional component of the endotoxin, which is released from the bacterial surface upon bacteria die or lyse. (People usually regard LPS as the endotoxin, in this manuscript, we regard both the dead bacteria-released LPS and PGN as the endotoxin) These free LPS/PGN can induce excessive inflammation and toxicity to the host. Therefore, targeting the key component of bacteria (LPS/PGN) may simultaneously inhibit bacterial survival and dead bacteria-induced excessive inflammation.
The dynamic borate ester bonds are widely used to identify glucose through the esterification reaction between boron dihydroxy group and 1,2-diol or 1,3-dial dihydroxyl groups of glucose9-11. Therefore, materials possessing boron dihydroxyl functional groups may react with LPS/PGN, as they also contain structures of 1,2-diol or 1,3-diol. However, such dynamic covalent bonds easily dissociate under acidic and inflammatory conditions. Hence, it is extremely necessary to design an antibacterial reagent that efficiently forms stable borate ester bonds with the key component of bacterial LPS/PGN, finally promoting wound healing.
Herein, we proposed a boron-trapping strategy and synthesized a class of nano-scale MB NPs (M=Mg, Al, and Be), using Nano-MgB2 as a representative example to elucidate the mechanism and function of MBs in promoting infected wound healing. The Nano-MgB2 are gradually hydrolyzed to generate boron dihydroxy groups and metal cations while generating a local alkaline microenvironment. This microenvironment greatly enhances boron dihydroxy groups to trap LPS or PGN through an esterification reaction, which not only enhanced metal cation-induced bacterial death but also inhibited dead bacteria-induced excessive inflammation both in vitro and in vivo, finally accelerating wound healing (Figure 2). Taken together, this boron-trapping strategy provides a new approach to the treatment of bacterial infection and the accompanying inflammation. The paper was published on Nature communications (Article link).
- Xue M, Zhao R, Lin H, Jackson C. Delivery systems of current biologicals for the treatment of chronic cutaneous wounds and severe burns. Adv Drug Deliv Rev 129, 219-241 (2018).
- Chin JS, Madden L, Chew SY, Becker DL. Drug therapies and delivery mechanisms to treat perturbed skin wound healing. Advanced Drug Delivery Reviews 149-150, 2-18 (2019).
- Ovington L. Bacterial toxins and wound healing. Ostomy Wound Manage 49, 8-12 (2003).
- Haidari H, et al. Multifunctional ultrasmall AgNP hydrogel accelerates healing of S. aureus infected wounds. Acta Biomater 128, 420-434 (2021).
- Sang Y, et al. Construction of Nanozyme‐Hydrogel for Enhanced Capture and Elimination of Bacteria. Advanced Functional Materials 29, 1900518 (2019).
- Kohanski MA, Dwyer DJ, Collins JJ. How antibiotics kill bacteria: from targets to networks. Nature reviews Microbiology 8, 423-435 (2010).
- Rippon MG, Westgate S, Rogers AA. Implications of endotoxins in wound healing: a narrative review. J Wound Care 31, 380-392 (2022).
- Saravanan R, et al. Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides. Nat Commun 9, 2762 (2018).
- Ni N, Laughlin S, Wang Y, Feng Y, Zheng Y, Wang B. Probing the general time scale question of boronic acid binding with sugars in aqueous solution at physiological pH. Bioorganic & Medicinal Chemistry 20, 2957-2961 (2012).
- Yuanyuan M, Hanting L, Jinghong M, Jinghua G. Glucose-responsive hydrogels based on phenylboronic acid. Materials Science Forum 913, 714-721 (2018).
- Marco-Dufort B, Tibbitt MW. Design of moldable hydrogels for biomedical applications using dynamic covalent boronic esters. Materials Today Chemistry 12, 16-33 (2019).