Synergistic phototherapy and Ca2+ consumption for combating biofilms in diabetic wounds via ion interference, physical disruption, and biological regulation

Multimodal treatment has become an essential strategy for addressing complex diabetic wound biofilm infections, which are resistant to conventional antibiotics and immune responses. Phototherapy including photodynamic therapy (PDT) and photothermal therapy (PTT) presents a highly promising solution. However, monomodal phototherapy often fails to fully eradicate resilient biofilms, as their dense extracellular polymeric substances (EPS) acts as a physical barrier. Ca²⁺ plays a crucial role in biofilm formation and bacterial structural integrity. A decrease in Ca²⁺ concentration destabilizes the biofilm, making it more susceptible to therapeutic interventions. Therefore, the multimodal treatment integrating PDT and PTT with Ca²⁺ consumption affords an appealing synergistic therapy. Herein, a wound dressing formed by a sodium alginate (SA)/polyacrylic acid (PAA)-based hydrogel encapsulating nanoparticles (NPs) of an aggregation-induced emission active photosensitizer (AIE-PS) is developed. The SA and PAA endows the dressing with biofilm Ca²⁺ consumption activity. The rationally designed AIE-PS with balanced energy dissipation in NPs can efficiently generate both reactive oxygen species (ROS) and heat under light exposure. Both <i>in vitro</i> and <i>vivo</i> experiments demonstrates that the multimodal approach exhibits potent antibacterial effects and accelerates diabetic wound healing <i>via</i> critical signaling pathways. This work proposes a multimodal therapy strategy by integrating ion interference-physical disruption-biological regulation into a single platform, offering a new paradigm for combating biofilms infected diabetic wounds while actively promoting tissue regeneration. Such a concept not only expands the potential of light-driven therapies in infected-wound care but also provides a blueprint for next-generation multifunctional materials through synergistic and programmable interactions.