Biofilm-triggered interfacial assembly of dual-porphyrin heterojunctions for chemo-/sonodynamic treatment of pyomyositis

Sonodynamic therapy (SDT) indicates advantages in combating antibiotics-resistant bacteria and deep tissue infections, but challenges remain in the development of highly efficient, infection-responsive, and biocompatible sonosensitizers. Herein, tetrakis (4-hydroxyphenyl) porphyrin (TH) and tetrakis (4-carboxyphenyl) zinc porphyrin (ZnTC) are proposed to construct dual-porphyrin heterojunctions (TH/ZnTC), and their matched interface and strong interfacial electric field (IEF) enhance charge density and transfer for selective and efficient SDT. Specifically, metal organic frameworks were constructed through coordination of Fe³⁺ and ZnTC and simultaneously loading TH to prepare TH@FeM. In infection sites with elevated glutathione, Fe³⁺ is reduced to Fe²⁺, triggering TH@FeM decomposition and TH/ZnTC self-assembly through π-π stacking and electrostatic interactions. IEF from ZnTC to TH drives the formation of S-scheme TH/ZnTC heterojunctions and greatly promotes efficient separation and transfer of the generated charges at the matched interface for efficient generation of reactive oxygen species. Meanwhile, GSH-reductive releases of Fe²⁺ enable high Fenton reaction activity for chemodynamic therapy. After intravenous injection into a mouse pyomyositis model, the enhanced penetration and retention in the infected muscles implements up to 3.1-folds higher fluorescence intensities than those of the major tissues. Ultrasonication of TH@FeM fully destructs bacteria, downregulates inflammatory factor levels, promotes angiogenesis, and accelerates healing of infected muscles without significant pathological and functional changes in the main organs, leading to continuous decreases in clinical scores and full survival of pyomyositis mice. Thus, the concise design represents the first attempt to explore biofilm-responsive heterojunction formation for synergistic chemo-/sonodynamic therapies of bacterial infections. STATEMENT OF SIGNIFICANCE: Nearly 80 % of chronic infections are linked to biofilm formation on living tissues. Extracellular polysaccharides produced by biofilms confer protection, making bacteria 10-1000 times more resistant to antibiotics compared to their planktonic counterparts, thus complicating treatment. Sonodynamic therapy (SDT) offers promising advantages in addressing antibiotics-resistant bacteria and deep tissue infections, but challenges remain in the development of highly efficient, infection-responsive, and biocompatible sonosensitizers. Herein, we propose biofilm-responsive generation of dual-porphyrin heterojunctions with matched interface and strong interfacial electric field, which enhance charge density and transfer for selective and efficient SDT. The glutathione-responsive formation and charge transfer mechanisms were both theoretically calculated and experimentally validated. Furthermore, target accumulation and treatment efficacy were demonstrated in a pyomyositis model.