Engineered Nile Red Derivatives‐Mediated Efficient Phototherapy Against Drug‐Resistant Bacteria and Monkeypox Virus

ABSTRACT The escalating threats of antimicrobial resistance and monkeypox virus infections pose a significant challenge to public health, necessitating innovative therapeutic approaches. Developing materials with balanced photodynamic and photothermal effects for the elimination of broad‐spectrum drug‐resistant bacteria and inactivation of the monkeypox virus remains a formidable task. Herein, we prepared a series of Nile Red derivatives by a donor rotation and charge transfer enhancement strategy, identifying 5‐(dicyanomethylene)‐9‐[4‐(bis(4‐methoxyphenyl)amino)phenyl]‐7a,12a‐dihydro‐5H‐benzo[a]phenoxazine (TPAOMCN)‐featuring alkoxy‐triphenylamine and malononitrile, as the optimal candidate. TPAOMCN demonstrated extended near‐infrared absorption, enhanced intersystem crossing (ISC) efficiency, and intense molecular motions, enabling dual‐modal phototherapy. Electrospun TPAOMCN nanofibers (NFs) with submicron‐scale diameter achieved >50°C temperature elevation and excellent reactive oxygen species (ROS) generation under irradiation. In methicillin‐resistant S. aureus (MRSA)‐induced wound infection and vaccinia virus‐mediated tail‐scarred models, TPAOMCN NFs effectively eliminated MRSA colonies and reduced viral load through physical disruption of pathogen membranes, thermal denaturation of viral capsids, and ROS‐mediated oxidation of biomolecules, while suppressing inflammation and accelerating angiogenesis‐mediated tissue repair. This study not only established a molecular engineering strategy for Nile Red to achieve prime PDT‐PTT performance but also provided a paradigm for advancing dual‐functional phototherapeutic platforms against emerging antimicrobial threats and monkeypox virus infections.