ABSTRACT Near‐infrared (NIR)‐II fluorescence imaging at 1000–1700 nm is widely used for deep‐tissue visualisation and disease theranostics in the brain, with NIR‐II theranostics greatly improving imaging resolution, imaging depth, and therapeutic efficacy. However, the extreme lack of molecular design in NIR‐II fluorophores has slowed the discovery of bright candidates and restricted their efficacious application in brain theranostics. Here, we develop a covalent bond locking (CBL) strategy that enables the feasible design of bright NIR‐II fluorophores by effectively restricting the twisted intramolecular charge transfer state. These spirofluorophores incorporate terminally spiro‐donor groups, which leads to a higher molar extinction coefficient and improved quantum yield than non‐spirofluorophores do. With bright and stable NIR‐II fluorescence advantages, we demonstrate that CBL nanoparticles (NPs) of spirofluorophores achieve multiscale high‐resolution NIR‐II angiography via one‐photon fluorescence and two‐photon fluorescence bioimaging simultaneously. With apolipoprotein E (ApoE) modification, CBL@ApoE NPs achieve enhanced blood‐brain barrier permeability, facilitating superior brain glioma theranostics. This work proposes a CBL strategy to engineer highly bright NIR‐II fluorescent fluorophores, providing a reliable nanoplatform for deep brain theranostics that can be effectively delivered across biological barriers to target brain tumors.
Li et al. (2026) studied this question.