Efficient NIR-II Type‑I AIE Photosensitizer for Mitochondria-Targeted Photodynamic Therapy through Synergistic Apoptosis–Ferroptosis

Hypoxia,
the hallmark of malignant tumors, has been recognized
as a major obstacle for photodynamic therapy (PDT). Precisely targeting
cancer cells in intricate biological scenarios by a hypoxia-resistant
photosensitizer (PS) is the cornerstone to conquer the inevitable
tumor recurrence and metastasis. Herein, we describe an organic NIR-II
PS (TPEQM-DMA) possessing potent type-I phototherapeutic efficacy
to overcome the intrinsic pitfalls of PDT in combating hypoxic tumors.
TPEQM-DMA exhibited prominent NIR-II emission (>1000 nm) with an
aggregation-induced
emission feature and efficiently produced superoxide anion and hydroxyl
radical in the aggregate state under white light irradiation exclusively
through a low-O2-dependent type-I photochemical process.
The suitable cationic nature assisted TPEQM-DMA to accumulate in cancerous
mitochondria. Meanwhile, the PDT of TPEQM-DMA impaired the cellular
redox homeostasis, led to the mitochondrial dysfunction, and raised
the level of lethal peroxidized lipids, which induced cellular apoptosis
and ferroptosis. This synergistic cell death modality enabled TPEQM-DMA
to suppress the growth of cancer cells, multicellular tumor spheroids,
and tumors. To improve the pharmacological properties of TPEQM-DMA,
TPEQM-DMA nanoparticles were prepared by encapsulation of polymer.
In vivo experiments proved the appealing NIR-II fluorescence imaging-guided
PDT effect of TPEQM-DMA nanoparticles for tumors.