Extended π‐Conjugated Bridge Strategy for an Enhanced Stokes Shift and Multimodal Imaging‐Guided Type I/II Photodynamic Therapy Integrated With Photothermal Therapy

ABSTRACT Phototheranostics represent a pivotal modality for the concurrent diagnosis and treatment of malignant tumors. The development of high‐performance phototheranostic agents has therefore become increasingly imperative. In this work, a “unity of a thousand blades” phototheranostic nanoplatform (TDTIC‐M) with aggregation‐induced emission (AIE) properties was synthesized through an extended electronic π‐bridge strategy to enhance the Stokes shift and multimodal image‐guided combined Type I/II photodynamic therapy and photothermal therapy (Type I/II PDT‐PTT) synergistic phototherapy for breast cancer. Specifically, the target compounds (TIC‐M, TTIC‐M, and TDTIC‐M) with donor‐acceptor distorted conformations were prepared by a Knoevenagel coupling reaction. The TDTIC‐M derivative, which incorporates two thiophene units as the π‐bridge, boasts enhanced optical characteristics relative to both TIC‐M and TTIC‐M. This derivative was further encapsulated within DSPE‐PEG 2000 to form TDTIC‐M nanoparticles (NPs) with good biocompatibility. Such NPs exhibit a large Stokes shift (∼270 nm), robust reactive oxygen species generation ( 1 O 2 , ·OH, and ·O 2 − ), and a notable photothermal conversion efficiency (27.93%). Furthermore, TDTIC‐M NPs demonstrate precise lysosome‐targeted capacity and excellent phototherapy effects in vitro and effectively regulate the expression of apoptosis‐related proteins (Caspase3, Bax, and Bcl‐2). Moreover, TDTIC‐M NPs demonstrate an exceptional multimodal imaging effect and synergistic phototherapy effect through integrating Type I/II PDT with PTT. Consequently, TDTIC‐M emerges as a highly prospective phototheranostic candidate for multimodal imaging‐guided cancer phototherapy.