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Abnormal physiological processes and diseases can lead to content or activity fluctuations of biocomponents in organelles and whole blood. However, precise monitoring of these abnormalities remains extremely challenging due to the insufficient sensitivity and accuracy of available fluorescence probes, which can be attributed to the background fluorescence arising from two sources, 1) biocomponent autofluorescence (BCAF) and 2) probe intrinsic fluorescence (PIF). To overcome these obstacles, we have re‐engineered far‐red to NIR II rhodol derivatives that possess weak BCAF interference. And a series of "zero" PIF sensing‐platforms were created by systematically regulating the open‐loop/spirocyclic forms. Leveraging these advancements, we devised various ultra‐sensitive NIR indicators, achieving substantial fluorescence boosts (190 to 1300‐fold). Among these indicators, 8‐LAP demonstrated accurate tracking and quantifying of leucine aminopeptidase (LAP) in whole blood at various stages of tumor metastasis. Furthermore, coupling 8‐LAP with an endoplasmic reticulum‐targeting element enabled the detection of ERAP1 activity in HCT116 cells with p53 abnormalities. This delicate design of eliminating PIF provides insights into enhancing the sensitivity and accuracy of existing fluorescence probes toward the detection and imaging of biocomponents in abnormal physiological processes and diseases. [ABSTRACT FROM AUTHOR]

Fluorescence imaging utilizing traditional organic fluorophores is extensively applied in both cellular and in vivo studies. However, it faces significant obstacles, such as low signal‐to‐background ratio (SBR) and spurious positive/negative signals, primarily due to the facile diffusion of these fluorophores. To cope with this challenge, orderly self‐assembled functionalized organic fluorophores have gained significant attention in the past decades. These fluorophores can create nanoaggregates via a well‐ordered self‐assembly process, thus prolonging their residency time within cells and in vivo settings. The development of self‐assembled‐based fluorophores is an emerging field, and as such, in this review, we present a summary of the progress and challenges of self‐assembly fluorophores, focusing on their development history, self‐assembly mechanisms, and biomedical applications. We hope that the insights provided herein will assist scientists in further developing functionalized organic fluorophores for in situ imaging, sensing, and therapy. [ABSTRACT FROM AUTHOR]

Abstract: Two‐photon imaging is an emerging tool for biomedical research and clinical diagnostics. Electron donor–acceptor (D–A) type molecules are the most widely employed two‐photon scaffolds. However, current D–A type fluorophores suffer from solvatochromic quenching in aqueous biological samples. To address this issue, we devised a novel class of D–A type green fluorescent protein (GFP) chromophore analogues that form a hydrogen‐bond network in water to improve the two‐photon efficiency. Our design results in two‐photon chalcone (TPC) dyes with 0.80 quantum yield and large two‐photon action cross section (210 GM) in water. This strategy to form hydrogen bonds can be generalized to design two‐photon materials with anti‐solvatochromic fluorescence. To demonstrate the improved in vivo imaging, we designed a sulfide probe based on TPC dyes and monitored endogenous H2S generation and scavenging in the cirrhotic rat liver for the first time. [ABSTRACT FROM AUTHOR]