Valence Electron Fluctuation in a High-Entropy Oxide Heterojunction Enables Collaborative Photodynamic and Mild-Thermal Therapy for Cutaneous Biofilm Infections

Mild photothermal therapy combined with photodynamic therapy has emerged as an effective treatment for antibiotic-resistant infection. However, controlling operation temperature within a safe range during reactive oxygen species (ROS) production remains a challenge. Herein, we present a functional heterojunction consisting of Ti₃C₂T_<i>x</i>-MXene and (CoCrFeMnNi)₃O₄ high-entropy oxide (HEO) featuring a valence electron fluctuation effect, achieving a highly efficient treatment of biofilm-associated infections in wounds and abscesses under mild conditions where skin temperature remains below 42.3 °C. We found that under near-infrared light irradiation, photogenerated hot electrons from MXene are efficiently transferred to the HEO surface, serving as abundant electron sources. The electron fluctuation effect of the HEO enables the rapid enrichment and activation of oxygen molecules in microenvironments, significantly enhancing ROS generation. Simultaneously, the built-in electric field at the MXene-HEO interface suppresses electron-hole recombination, minimizing excessive heat generation and ensuring efficient photothermal-photodynamic synergy. The accelerated generation of ROS inhibits the synthesis of adenosine triphosphate (ATP) by disrupting the bacterial respiratory chain complex (RCC), which significantly inhibits the expression of ATP-dependent molecular chaperone genes <i>groEL</i> and <i>ClpP</i>, compromising bacterial heat resistance and virulence to achieve mild thermal therapy. Moreover, it also shows superior benefits in tissue regeneration, collagen deposition, and angiogenesis while alleviating the inflammation, exhibiting a robust solution for drug-resistant bacterial biofilms in cutaneous tissues. Our work highlights the potential of HEO functional heterojunctions for safe and effective mild-temperature biomedical therapies and paves the way for advanced strategies in combating biofilm-associated infections through rational material design and engineering.