Abstract Organic nanomedicines integrating second near‐infrared (NIR‐II) fluorescence imaging and photodynamic therapy (PDT) hold substantial potential for precise cancer phototheranostics. However, the competing mechanisms between NIR‐II fluorescence emission and phototherapeutic effects pose a fundamental optimization challenge for their concurrent application. To address this, we propose an innovative fluorination strategy by constructing fluorinated surroundings in NIR‐II‐emissive organic semiconducting agents to synergistically amplify cancer phototheranostics. Our exploiting versatile theranostic agent synergistically combines fluorinated nanocarriers with organic semiconducting photosensitizers, leveraging fluorine's unique physicochemical properties to achieve synergistic‐amplification multimodal functionality. The hydrophobic and oleophobic nature of fluorine atoms creates isolated microenvironments for phototheranostic molecule, effectively mitigating molecular aggregation and minimizing interactions with external quenchers, namely the two major factors responsible for fluorescence quenching. Consequently, this structural optimization significantly enhances 2.3‐fold NIR‐II fluorescence brightness. Additionally, the hydrophobic microenvironment constructed by fluorine‐rich polymer carriers minimizes oxygen diffusion loss, imparting superior oxygen‐capturing capacity to this nanosystem. This potently overcomes hypoxia limitations in conventional PDT and significantly enhances singlet oxygen generation efficiency by 61.25%. Collectively, this rationally designed platform enables NIR‐II fluorescence‐guided synergistic PDT and photothermal therapy, effectively overcoming the performance trade‐offs in conventional phototheranostics. Our fluorine‐engineered approach establishes a novel paradigm for developing new‐generation nanotheranostic systems.
Cui et al. (Sun,) studied this question.