A Novel Approach Based on Acceptor–Donor–Acceptor Type Molecules Enhances the Therapeutic Efficacy and Safety of Photothermal Therapy for Osteosarcoma

ABSTRACT Photothermal therapy based on acceptor–donor–acceptor (A‐D‐A) type molecules is emerging as a powerful clinical treatment strategy, yet its potential application in malignant osteosarcoma has been scarcely investigated. To resolve this, we constructed novel photothermal reagents from A‐D‐A molecules, boosting PCE of A‐D‐A photosensitizers by regulating intramolecular push–pull interactions. Through an optimized push–pull architecture, the IEICO‐F molecule achieved an ideal overlap between its absorption spectrum and the 808 nm NIR laser, along with a high absorption coefficient and an increased nonradiative decay rate constant. Accordingly, following 5‐min 808 nm laser exposure (0.33 W cm ^{− 2} ), the temperature of IEICO‐F nanoparticles climbed to 63.8°C, exceeding IEICO nanoparticles by 9.2°C. These nanoparticles effectively generated heat to kill osteosarcoma cells and exhibited significant tumor suppression in osteosarcoma models. Importantly, our molecular design also ensures good safety profiles for practical medical application. Therefore, this novel A‐D‐A type molecule‐based photothermal therapy strategy holds promise for widespread clinical use in osteosarcoma treatment and may be extendable to other tumor types in the future.