Ultrasound-responsive metastable copper/zinc-polyphenol framework for targeted anti-infection of diabetic wounds

The management of drug-resistant bacterial biofilm infections in diabetic wounds is a major clinical challenge. Although copper-ion-based antimicrobials are widely used in disinfection, their clinical applications are limited because uncontrolled, non-targeted and excess copper ions pose significant biosafety risks. Here, we develop an ultrasound (US)-gated metastable copper antibacterial platform (Cu/Zn-polyphenols). It is found that Zn²⁺ doping can construct a metastable Cu²⁺ structure by changing its coordination environment in polyphenol. The metastable Cu²⁺-polyphenol coordination can be disrupted under US because Zn²⁺ promotes the US-activated electron transfer, which facilitates the rapid reduction of Cu²⁺ to Cu⁺ and enables the controllable release of Cu⁺. The selected Cu/Zn-lignosulfonate (Cu/Zn-Ls) exhibits a stronger binding affinity to bacterial cell membranes than to mammalian cell membranes. Under US, the targeted and rapid accumulation of Cu⁺ inside bacteria impedes the bacterial energy metabolism network (antibacterial efficiency >99%). Besides Cu/Zn-Ls, Cu/Zn-dopamine and Cu/Zn-tannin also show great antibacterial ability, proving the generalizability of Cu/Zn-polyphenol antibacterial platform. MRSA infected diabetic wounds in mice and mini-pigs were established, the Cu/Zn-Ls loaded microneedles accelerate the wounds healing through US therapy. This work changes the traditional usage of copper antimicrobials, facilitating their clinical application.