LAUSR

Infections caused by drug‐resistant bacteria represent a major contributor to high mortality rates, underscoring the urgent need for effective non‐antibiotic drugs and alternative therapies. Antimicrobial photodynamic therapy (aPDT) emerges as an innovative treatment due to its minimal drug resistance. Herein, a series of Nile Red derivatives is synthesized by a donor engineering strategy. Notably, NTPA featuring triphenylamine (TPA) as the electron‐donating group, exhibited the highest production of reactive oxygen species (ROS). The enhanced electron donating‐accepting (D‐A) property effectively reduced the energy gap between S1 and T1 (ΔES‐T), facilitating intersystem crossing (ISC) with a larger spin‐orbit coupling (SOC) constant. Furthermore, the twisted conformation profoundly suppressed the quenching of ROS. As expected, an over 470‐fold increase in ROS production is observed, predominantly comprising type‐I ROS. NTPA nanoparticles (NPs) exhibited exceptional in vitro killing ability against various drug‐resistant bacteria, with inhibition efficiency even reaching 99.9%. In the methicillin‐resistant staphylococcus aureus (MRSA)‐induced abscess model, NTPA NPs facilitated complete wound healing within just 8 days following a single administration and irradiation, highlighting their exceptional bactericidal and wound‐healing promotion capabilities. Overall, this work inspired the construction of efficient Nile Red‐based type‐I photosensitizers (PSs) and the development of a new broad‐spectrum aPDT method for drug‐resistant bacteria treatment.