A “Jack-of-All-Trades” Phototheranostic System Enabled by Strategic Regulation of Ferroptosis and PANoptosis for Cancer Therapy

Phototheranostic strategies for cancer remain constrained by the availability of phototheranostic agents. Nonfullerene acceptor (NFA) materials, characterized by their distinctive structure and optical characteristics, emerge as promising candidates for the high-performance phototheranostic agents. In this work, an A-D-A'-D-A type NFA material (DB-QX-asy-4F) was designed as a phototheranostic agent to facilitate a comprehensive therapeutic effect on breast cancer by integrating the mechanisms of ferroptosis and PANoptosis. Briefly, the DB-QX-asy-4F and DSPE-mPEG-cRGD form biocompatible nanoparticles DB-QX-asy-4F NPs through self-assembly. Such NPs displayed strong emission fluorescence that redshifts to the NIR-II region, a large Stokes shift of 235 nm, and a quantum yield of 1.97%. Furthermore, DB-QX-asy-4F NPs enables the realization of precise tumor localization, high-resolution fluorescence imaging, photoacoustic imaging, and clear vascular imaging. These NPs generated both type I (^•O₂^-, ^•OH) and type II (¹O₂) reactive oxygen species (ROS), and exhibited super photothermal conversion efficiency of 48.49%, endowing it with a synergistic photodynamic therapy (PDT)-photothermal therapy (PTT) capability to effectively suppressing tumor growth. Mechanistically, the therapeutic effects were mediated primarily through the regulation of ferroptosis and PANoptosis pathways. Overall, this system offers innovative insights for advancing the development of phototheranostic agent and enhancing the understanding of their underlying molecular mechanisms.