Peripheral structural engineering of quinoline-malononitrile-triphenylamine (QM-TPA) core enhances Anti-tumor PDT efficacy through necroptosis.

To circumvent the limitations of aggregation-caused quenching (ACQ) associated with conventional photosensitizers (PSs), we sought to develop PSs based on aggregation-induced emission luminogens (AIEgens). Through molecular hybridization of a quinoline-malononitrile (QM) acceptor and a triphenylamine (TPA) unit, along with systematic SAR exploration of N-atom substitutions on the QM core, we generated a series of AIE-active PSs. Among these, A04 emerged as the lead, exhibiting potent Type I ROS generation, a high safety profile (selectivity index >158), and remarkable specificity for the endoplasmic reticulum (ER) (Pearson correlation coefficient = 0.91). Critically, this subcellular localization underpins its mechanism of action: by generating ROS within the ER, A04 induces necroptosis. Consequently, A04 demonstrates robust antitumor PDT activity both in vitro and in a 4T1 murine model. This study thus validates A04 as a therapeutically promising, rationally designed AIEgen-PS.