Molecular Engineering of AIE‐Active Ionic Photosensitizer for Dual‐Organelle Targeted NIR‐II Phototheranostics

Abstract Fluorescence imaging (FLI)‐guided photodynamic therapy (PDT) has emerged as a promising strategy for precision cancer treatment. However, the rational design of phototheranostic agents integrating long‐wavelength emission, efficient reactive oxygen species (ROS) generation, and precise organelle targeting remains a formidable challenge. In this study, quantum chemistry and dynamics simulations are employed to predict that a donor‐π‐acceptor (D‐π‐A) architectural framework can systematically modulate excited‐state properties to achieve optimal photophysical characteristics. Guided by these theoretical insights, a series of second near‐infrared (NIR‐II) emissive ionic photosensitizers featuring aggregation‐induced emission (AIE) characteristics is designed and synthesized. The optimized compound, BuDTTPy, exhibited exceptional performance, including a large Stokes shift (280 nm), distinct AIE behavior, strong NIR‐II fluorescence (Φ = 6.14%), and highly efficient ROS generation. Experimental results revealed that BuDTTPy nanoparticles (NPs) possess remarkable photostability, excellent biocompatibility, and dual‐targeting capability toward mitochondria and endoplasmic reticulum. Leveraging these advantages, NIR‐II FLI‐guided dual‐organelle‐targeted PDT is successfully implemented, achieving potent therapeutic efficacy in an orthotopic breast cancer mouse model. This work not only experimentally validates theoretical predictions of superior photophysical properties in AIE materials, but also establishes a novel paradigm for developing organelle‐precision phototheranostic systems.