TWEAK-Conjugated Selenoviologen as a Novel Photosensitizer for Selective Wound Accumulation and Synergistic Healing of Drug-Resistant Bacterial Infections
Skin wounds are refractory due to antibiotic-resistant bacterial infection. Although photodynamic therapy (PDT) offers noninvasiveness, high efficiency, and no drug resistance, its therapeutic effect is constrained by the complex structure of wound tissue and diffuse drug distribution. The proinflammatory cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) regulates tissue repair by engaging its receptor Fn14, which is highly expressed in wounds. In this study, we developed a novel photosensitizer, the selenoviologen-TWEAK conjugate (SeV-Tp), to enhance selective enrichment and synergistically promote wound healing. In vitro analyses demonstrated that SeV-Tp, under visible light, generated high levels of reactive oxygen species, resulting in potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Notably, SeV-Tp selectively bound to Fn14 and amplified fibroblast activation via photodynamic cooperation. In a mouse model of antibiotic-resistant Pseudomonas aeruginosa-infected wound, SeV-Tp accelerated healing by reducing bacterial burden, modulating the immune microenvironment, promoting collagen deposition, and stimulating hair follicle regeneration. Moreover, SeV-Tp preferentially accumulated within wound tissues with minimal adverse effects. SeV-Tp represents a strategy that selectively enriches and harnesses synergistic benefits from both components, positioning SeV-Tp as a promising photosensitizer for the treatment of refractory wounds.