Skin-inspired phototherapeutic cryogel ameliorates infected wound healing by orchestrating mechanotransduction and immunomodulation

Skin rehabilitation in clinics is seriously threatened by chronic wounds developed from drug-resistant bacteria, such as methicillin-resistant <i>Staphylococcus aureus</i> (<i>MRSA</i>), which frequently exhibit delayed healing owing to the hyperactive pro-inflammatory response, oxidative stress amplification, and fibrosis induction. Inspired by the skin epidermis, herein, we developed a deoxyribonucleic acid (DNA)/gelatin methacrylate (GelMA)-based soft cryogel platform that incorporates metal-organic framework (MOF) decorated plasmonic Ti₃C₂T_x (MXene) as a photosensitizer to prevent <i>MRSA</i> infection and promote scarless wound healing. By leveraging the bioactive and near-infrared (NIR) responsive property of the cryogel, mild phototherapy resulted in robust bactericidal performance and functional tissue regeneration while attenuating oxidative stress and maintaining hydrophilicity. Additionally, the transcriptome study verified that photobiomodulation by cryogel increased signature biomarkers that activate cytokeratin and zinc finger proteins owing to the Zn²⁺ ion adsorption to keratinocytes, highlighting its significant role in wound remodeling. Consequently, <i>in vivo</i> studies further disclose that cryogel-induced photobiomodulation promotes angiogenesis, thick epidermis generation, superior granulation, hair follicle growth, and anti-inflammatory activation without scarring, comparable to native skin. These findings underscore the remarkable potential of the fabricated cryogel as an innovative wound dressing material, providing an irresistible solution for managing infected skin wounds.