Engineering a Near-Infrared\nSpiro-Based Aggregation-Induced\nEmission Luminogen for DNAzyme-Sensitized Photothermal Therapy with\nHigh Efficiency and Accuracy

Aggregation-induced emission luminogen (AIEgens)-based\nphotothermal\ntherapy (PTT) has grown into a sparkling frontier for tumor ablation.\nHowever, challenges remain due to the uncoordinated photoluminescence\n(PL) and photothermal properties of classical AIEgens, along with\nhyperthermia-induced antiapoptotic responses in tumor cells, hindering\nsatisfactory therapeutic outcomes. Herein, a near-infrared (NIR) spiro-AIEgen <b>TTQ-SA</b> was designed for boosted PTT by auxiliary DNAzyme-regulated\ntumor cell sensitization. <b>TTQ-SA</b> with a unique molecular\nstructure and packing mode was initially fabricated, endowing it with\na strong AIE effect, favorable PL quantum yield, and good photothermal\nperformance. DNAzyme, as a gene silencing tool, could alleviate antiapoptosis\nresponse during PTT. By integrating <b>TTQ-SA</b> and DNAzyme\ninto folate-modified poly(lactic-<i>co</i>-glycolic acid)\n(PLGA) polymer, the as-fabricated nanosystem could promote cell apoptosis\nand sensitize tumor cells to PTT, thereby maximizing the therapeutic\noutcomes. With the combination of spiro-AIEgen-based PTT and DNAzyme-based\ngene silencing, the as-designed nanosystem showed promising NIR and\nphotothermal imaging abilities for tumor targeting and demonstrated\nsignificant cell apoptotic, antitumor, and antimetastasis effects\nagainst orthotopic breast cancer. Furthermore, a synergistic antitumor\neffect was realized in spontaneous MMTV-PyMT transgenic mice. These\nfindings offer new insights into AIEgen-based photothermal theranostics\nand DNAzyme-regulated tumor cell sensitization, paving the way for\nsynergistic gene silencing-PTT nanoplatforms in clinical research.