Dual-target regulation of glutathione and heat shock proteins <i>via</i> molecular-carrier-pathway triple-engineering for potentiated phototherapy

Photodynamic therapy (PDT) and photothermal therapy (PTT) face efficacy limitations due to overexpressed glutathione (GSH) and activated heat shock proteins (HSPs). Here, we synthesized a multifunctional agent N3-4F (N3) through molecular engineering. Leveraging strong acceptor-donor (A-D) interactions and reduced singlet-triplet energy gap (Δ<i>E</i>_S-T), N3 demonstrated exceptional type I/II reactive oxygen species (ROS) generation. An extended π-conjugated backbone with long alkyl chains enhanced light absorption and conferred a remarkable photothermal conversion efficiency (PCE) of 44.9%. To overcome tumor microenvironmental limitations, we engineered a disulfide bond-integrated nanocarrier and co-delivered HSP inhibitor KNK437 (437), selectively depleting intracellular GSH while disrupting thermoresistance. <i>In vivo</i> studies revealed that N3@437 under 808 nm laser irradiation achieved 94.9% tumor growth inhibition and markedly suppressed lung metastasis. By employing a triple-pronged strategy of molecular engineering, nanocarrier design, and pathway blockage, this work pioneered a paradigm that concurrently depletes GSH and inhibits HSPs. This breakthrough enables enhanced PDT/PTT performance, offering a transformative solution for combating tumor adaptive resistance.