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-PEG2000, 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 H2O2, 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.