Molecular‐Twist‐Engineered Non‐Fullerene Acceptor Type Organic Sonosensitizers with Enhanced Intersystem Crossing for Highly Effective Sonodynamic Therapy of Large Solid Tumors

Near‐infrared (NIR)‐emissive sonosensitizers hold significant potential for precision imaging‐guided sonodynamic therapy (SDT), yet their development remains challenging due to typically poor sonosensitizing efficiency. In this work, a non‐fullerene acceptor (NFA) type organic sonosensitizer STS‐TPE is first designed for large scale solid tumor sonodynamic therapy. The multi‐intramolecular charge transfer (ICT) effect and intentionally engineered molecular twist synergistically enable strong NIR emission (842 nm), a narrowed singlet‐triplet energy gap (Δ E st ), and enhanced intersystem crossing (ISC), leading to superior SDT performance. Mechanistic studies confirm that ultrasound (US) irradiation triggers simultaneous reactive oxygen species (ROS) generation and mild hyperthermia, offering a combined therapeutic effect. Benefiting from the good penetration ability, STS‐TPE achieves efficient tumor cell suppression even under 1 cm‐thick biological tissue (chicken breast). Moreover, in vivo NIR imaging of solid tumor with the signal/noise ratio of 3.7 is achieved. Remarkably, a single US‐triggered SDT treatment with STS‐TPE effectively inhibits the growth of large solid tumors in vivo, highlighting its clinical potential. This work provides a general molecular design strategy to overcome the limitations of conventional sonosensitizers for treating deep‐seated tumors.