Nucleus‐Targeting Photosensitizers Enhance Neutrophil Extracellular Traps for Efficient Eradication of Multidrug‐Resistant Bacterial Infections

Abstract Neutrophil extracellular traps (NETs) are web‐like complexes of DNA and proteins that are extruded by activated neutrophils and play critical roles as major components of the innate immune response against pathogen invasion. However, some microbes have developed strategies to evade NET attacks, leading to impaired immune defenses and persistent infections. In this study, an engineered neutrophil strategy for enhancing the antibacterial activity of NETs is developed. A nucleus‐targeting photosensitizer (NCP) with strong reactive oxygen species production and a strong DNA‐binding capacity is synthesized. NCP‐loaded neutrophils are subsequently constructed via direct incubation of NCP with neutrophils, and the NCP is closely inserted into the nucleus DNA. Upon activation by bacteria‐related toxins, NCP‐coupled NETs can be released rapidly, actively trapping bacteria and providing a high local concentration of NCP around them. Both in vitro and in vivo results revealed that NCP‐coupled NETs can effectively eradicate various multidrug‐resistant bacteria and biofilms through photodynamic therapy, overcome bacterial immune evasion, and promote tissue recovery from severe wound infections. This design can significantly strengthen NET function, providing a non‐antibiotic alternative platform for treating bacterial infectious diseases.