综述：针对线粒体的光敏剂材料在氧化应激介导的癌症治疗及其他领域的应用

线粒体靶向聚集诱导发光（AIE）材料通过可控诱导氧化应激，在直接抗肿瘤、协同化疗/放疗/免疫治疗、神经保护及抗真菌等领域展现潜力，机制涵盖凋亡、自噬、焦亡等细胞死亡途径及肿瘤相关蛋白降解。

　　

mitochondria-targeted AIE materials have emerged as a groundbreaking class of therapeutic agents by enabling precise and controlled induction of oxidative stress within mitochondria. This review systematically explores the mechanisms and applications of such materials across diverse therapeutic domains, emphasizing their potential to address both cancer and non-cancer diseases through nuanced regulation of cellular redox states.### Oxidative Stress as a Double-Edged Sword

Oxidative stress, originally recognized as a harmful consequence of excessive reactive oxygen species (ROS) production, has been redefined as a biologically regulated modulator of cellular homeostasis. While excessive ROS induces DNA damage and mitochondrial dysfunction leading to cell death, controlled activation of mild oxidative stress can stimulate cell signaling pathways, promote protein degradation, and regulate metabolic processes. This duality positions mitochondria-targeted AIE materials as versatile tools for therapeutic intervention.### Unique Advantages of AIE Materials

AIE materials, characterized by their aggregation-induced emission properties, offer distinct advantages over conventional photosensitizers:

1. **Structural Features**: Twisted molecular frameworks and steric hindrance prevent aggregation in solution, ensuring only aggregated forms in biological systems can emit light and generate ROS.

2. **ROS Generation Efficiency**: Mitochondrial targeting allows AIE materials to concentrate ROS production in organelles with high transmembrane potential, enhancing therapeutic specificity.

3. **Modulability**: Adjusting light parameters (intensity, wavelength, duration) enables precise control over ROS levels, which determines whether cells undergo apoptosis, autophagy, or other death pathways.### Direct Antitumor Effects Through Oxidative Stress

#### 1.1 Apoptosis Induction

AIE materials like TPE-Py and TBTP selectively accumulate in mitochondrial membranes of cancer cells. Upon light activation, they generate excessive ROS, leading to cytochrome c release, mitochondrial membrane potential collapse, and activation of caspase-3/9 pathways. For example, Ru2 complexes deplete NADH, creating an imbalance that amplifies ROS production, triggering apoptosis in A549 cells. Innovations such as GSH-responsive click-activated AIE materials (TPATrzPy-3?) enhance this effect by preferentially targeting tumor mitochondria under low pH conditions.#### 1.2 Autophagy and Mitophagy Modulation

Materials like DP-PPh3 disrupt autophagic flux by blocking p62 degradation, causing damaged organelles to accumulate. Conversely, TACQ and Ru-TPE-PPh3 induce mitophagy through ROS-mediated mitochondrial damage, leading to pyroptosis. These dual actions—triggering cell death while clearing受损 organelles—overcome drug resistance mechanisms.#### 1.3 Pyroptosis Activation

Th-M and TPA-2TIN induce pyroptosis by cleaving gasdermin D (GSDMD) and releasing inflammatory mediators. This pathway is particularly effective in immunosuppressive tumor microenvironments, where immune cell recruitment is enhanced through cytokine release.#### 1.4 Protein Degradation

AIE materials like DPA-B-YP+ leverage oxidative stress to downregulate tumor-associated proteins. By inducing moderate mitochondrial ROS, they activate AMPK-dependent ubiquitination pathways, efficiently degrading PD-L1 and mutp53, thereby sensitizing tumors to immunotherapy and chemotherapy.### Synergistic Therapeutic Applications

#### 2.1 Chemo- and Radiotherapy Enhancement

AIE materials synergize with conventional therapies by sensitizing cells to treatment. For example, TPE-Py combined with paclitaxel reduces IC50 by 50-fold, while DFL NPs combined with RT achieve a sensitization ratio of 2.96. This is achieved through mitochondrial ROS-mediated inhibition of DNA repair mechanisms and enhancement of radiation-induced DNA breaks.#### 2.2 Immunotherapy Augmentation

DCTIC NPs and DEV-AIE platforms trigger immunogenic cell death (ICD) by exposing calreticulin and HMGB1 on cell surfaces. These DAMPs activate dendritic cells and natural killer cells, leading to tumor-specific T-cell responses. In murine models, such combinations achieve 100% survival rates in some cases.#### 2.3 Multimodal Therapy Integration

AIE materials enable synergistic combinations with emerging therapies:

- **Photothermotherapy**: PMTi NPs combine PDT with photothermal effects, achieving 70% tumor necrosis with lower doses than monotherapy.

- **Gas Therapy Synergy**: TPyNO-FeCO NPs amplify ROS production through CO release, creating a self-reinforcing "ROS-CO-ROS" cycle that enhances PDT efficacy by 2.5-fold.### Beyond Cancer: Non-Oncological Applications

#### 3.1 Neuroprotection

DTCSPY NPs protect neuronal cells and stem cells from oxidative damage by activating cytoprotective autophagy. This mechanism counteracts H2O2-induced toxicity while preserving normal cellular functions.#### 3.2 Antifungal Therapy

IQ-TPA materials overcome drug resistance by targeting fungal mitochondria. Under 660 nm irradiation, they generate singlet oxygen that disrupts fungal cell membranes and cytochrome oxidase, achieving 100% inhibition of candidiasis in animal models.### Technical Challenges and Future Directions

Current limitations include:

1. **Subcellular Localization Uncertainty**: Most studies rely on mitochondrial trackers rather than direct imaging of ROS production in specific mitochondrial compartments (matrix, inner/outer membrane).

2. **Mechanistic Gaps**: The precise molecular cascades linking ROS to protein modifications (e.g., sulfenylation, glutathionylation) remain unclear.

3. **Tissue Penetration Issues**: Light-based activation limits deep tissue applications. Ultrasound-activated AIE materials (TCSVP) show promise but require further optimization.

4. **Biomaterial Design**: Current carriers lack precise release controls. Hydrogel systems (TSH) demonstrate potential but need improved biocompatibility.Future research should focus on:

- **Precision Targeting**: Designing AIE materials that distinguish between healthy and pathological mitochondria using redox state-specific targeting.

- **Multi-Parameter Control**: Developing systems that allow simultaneous regulation of ROS type (·OH, O2?•, 1O2), concentration, and duration.

- **Long-Term Safety Studies**: While AIE materials show low toxicity, chronic exposure effects and mitochondrial dependency in normal cells require evaluation.### Conclusion

Mitochondria-targeted AIE materials exemplify the convergence of material science and cell biology. Their ability to control oxidative stress spatiotemporal distribution addresses a critical challenge in precision medicine—avoiding off-target damage while maximizing therapeutic efficacy. As research progresses, these materials hold potential to revolutionize treatments for not only cancers but also neurodegenerative diseases, infections, and metabolic disorders, provided technical challenges in material design and clinical translation are overcome.