Succinct NIR-II absorbed croconic acid-julolidine molecule uniting Fe (III)-quercetin complex for efficient mild photothermal therapy of oropharyngeal carcinoma

The development of non-invasive mild photothermal therapy (MPTT) in combating oropharyngeal carcinoma (OC) can bring safe and effective for patients, and keep maximum preservation of oral function. In this study, we successfully synthesized a novel croconic acid-julolidine molecule (Cro-Jul) with broad absorption in the second near -infrared (NIR-II, 900 - 1700 nm) region, which is accompanied with high photothermal conversion efficiency (PCE) and controllable photothermal capacity. By systematically molecular theoretical calculation, the NIR-II optical properties of Cro-Jul and its photothermal conversion mechanism were analyzed. Besides, a coordination bond between quercetin (Qu) and Fe(III) was created to form a Fe(III)-Qu complex that not only can enhance MPTT by reducing heat shock proteins (HSPs) expression but also can introduce ferroptosis/chemodynamic therapy (CDT) for better therapeutic effect. By incorporating Cro-Jul and Fe(III)-Qu with DSPE-PEG 2000 , the multifunctional Fe(III)-Qu/CJ nanosystem was formed with an impressive PCE of 48.96 % under 980 nm irradiation, and the released Qu from the nanosystem effectively suppresses HSP70 expression during MPTT progress. Concurrently, liberated Fe(III) from the nanosystem interacts with intracellular glutathione and H 2 O 2 , inducing ferroptosis and CDT in tumor cells, ultimately enhancing apoptosis. Consequently, this study introduces a novel organic Cro-Jul molecule with Fe(III)-Qu nanosystem that combines ferroptosis, CDT, and NIR-II MPTT guided by photoacoustic imaging, offering significant potential for future clinical applications in OC treatment.