Sonocatalytic hydrogen/hole-combined therapy for anti-biofilm and infected diabetic wound healing

It is a great challenge to effectively eradicate biofilm and cure biofilm-infected diseases because dense extracellular polymeric substance matrix prevents routine antibacterial agents from penetrating into biofilm. H(2) is an emerging energy-regulating molecule possessing both high biosafety and high tissue permeability. In this work, we propose a concept of sonocatalytic hydrogen/hole-combined ‘inside/outside-cooperation’ anti-biofilm for promoting bacteria-infected diabetic wound healing based on two-dimensional piezoelectric nanomaterials. Proof-of-concept experiments using C(3)N(4) nanosheets as a representative piezoelectric catalyst with wide band gap and high biosafety have verified that sonocatalytically generated H(2) and holes rapidly penetrate into biofilm to inhibit bacterial energy metabolism and oxidatively deprive polysaccharides/NADH in biofilm to destroy the bacterial membrane/electron transport chain, respectively, inside/outside-cooperatively eradicating biofilm. A bacteria-infected diabetic wound model is used to confirm the excellent in vivo antibacterial performance of sonocatalytic hydrogen/hole-combined therapy, remarkably improving bacteria-infected diabetic wound healing. The proposed strategy of sonocatalytic hole/hydrogen-combined ‘inside/outside-cooperation’ will make a highway for treatment of deep-seated biofilm infection.