Rational Design of Organic Chromophores for Simultaneously Trig‐gering Redox Imbalance and Tracking Organelles in Biological Sys‐tems Under Near‐Infrared Light Irradiation

The design of organic photosensitizers that operate efficiently in the near‐infrared (NIR) region remains challenging due to the need to balance electronic delocalization, stability, and biological compatibility. Here we report a rational, electronegativity‐guided strategy for engineering (donor–π) 3 –acceptor pyrylium‐based chromophores capable of concurrent NIR phototherapy and subcellular imaging. Density functional theory calculations identified pyrylium (PYR) as the optimal acceptor for narrowing the HOMO–LUMO gap and enhancing intramolecular charge transfer (ICT). The resulting octupolar chromophores, PYR‐OMe and PYR‐NPh 2 , display intense absorption in the 600–800 nm range, large Stokes shifts (>100 nm), and excellent photostability. Under NIR irradiation, PYR‐NPh 2 catalyzes efficient NADH photooxidation and generates multiple reactive oxygen species (ROS), even under hypoxic conditions. In cancer cells (e.g., MDA‐MB‐231), PYR‐NPh 2 induces redox imbalance and pronounced phototoxicity while enabling high‐fidelity lysosomal imaging at ∼100 nm resolution using structured illumination microscopy. This work introduces a unified molecular design principle for NIR organic chromophores that integrate redox modulation, ROS generation, and organelle‐level visualization, advancing the frontier of precision phototheranostics.