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. Bothin vitroandvivoexperiments demonstrates that the multimodal approach exhibits potent antibacterial effects and accelerates diabetic wound healingviacritical 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.A multimodal treatment integrating photodynamic therapy (PDT), photothermal therapy (PTT), and Ca2+consumption is developed using an AIE-PS nanoparticle-encapsulated sodium alginate/polyacrylic acid hydrogel dressing (TSCNPy2+-NPs@SA/PAA). This approach disrupts biofilms, enhances antibacterial efficacy, and accelerates diabetic wound healing by generating ROS and heat, while activating PI3K/AKT, JAK/STAT, and MAPK pathways to promote cell proliferation, migration, and angiogenesis.Image 1View The PDF