Sonodynamic therapy (SDT) is an effective treatment for refractory triple-negative breast cancer (TNBC) by generating toxic reactive oxygen species (ROS) within tumors. However, its therapeutic efficacy is limited by the fact that cancer cells reduce mitochondrial oxidative damage through the mitophagy mechanism. Here, we report an all-in-one tumor therapy strategy that combines nanosonosensitizer-enhanced noninvasive SDT with autophagy inhibition. This strategy is achieved by rationally constructing a sonosensitizer liquid Z-type heterojunction, which consists of two sonosensitizer PtCu3 nanocages and autophagy-inhibiting BP nanosheets connected by a hydrophilic organic linker (PEI-PEG5000-C18). Conjugated electron mediators (M, Cp*Rh(phen)Cl) are strategically placed between the two sonosensitizers to facilitate electron transfer. The M-based Z-type heterojunction structure prolongs the separation time of sonosensitizer electron-hole pairs, enabling efficient ROS generation under ultrasound stimulation. More importantly, the Cu2+ released from PtCu3 accelerates BP degradation by reducing the phosphorus vacancy formation energy, improves the biodegradability of BP-M-PtCu3, and promotes the generation of phosphate ions. These ions increase the lysosomal pH and inhibit the hydrolysis of damaged mitochondria in autophagic lysosomes, thereby preventing cancer cells from self-protecting under oxidative stress and effectively eliminating TNBC. It is believed that the M-based sonosensitizer-based sonosensitizer Z-type heterojunction will become a promising sonosensitizer structure, and the sonodynamic autophagy inhibition strategy provides valuable prospects for cancer treatment.

Innovation:
1. An innovative therapeutic strategy is proposed to overcome the mechanism of cancer cells' self-protection through mitochondrial autophagy by combining nanosonosensitizer-enhanced sonosensitizer with autophagy inhibition, thereby improving the therapeutic effect.
2. A M-based sonosensitizer-based sonosensitizer Z-type heterojunction is constructed, combining PtCu3 nanocages and BP nanosheets with electron mediator Cp*Rh(phen)Cl to promote electron transfer and ROS generation.
3. The Cu2+ released by the PtCu3 nanocage accelerated the degradation of BP, improved the biodegradability of the BP-M-PtCu3 system, and promoted the generation of phosphate ions.
4. The generated phosphate ions inhibited the hydrolysis of damaged mitochondria by increasing the pH of lysosomes, thereby preventing cancer cells from self-repairing through the autophagy mechanism.

Inspiration for scientific research:
1. The relationship between sonodynamic therapy and cell autophagy can be further explored, and how to use different treatment methods in combination to maximize the therapeutic effect.
2. By designing nanomaterials with multiple functions, such as the Z-type heterojunction in this study, different therapeutic effects can be achieved in the same system.
3. By in-depth research on how to break the drug resistance mechanism of tumor cells, especially mitochondrial autophagy and self-repair mechanism, new ideas and strategies can be provided for the precision treatment of cancer and the treatment of drug-resistant tumors.

Idea extension:
1. In addition to sonodynamic therapy, other treatment methods (such as photodynamic therapy, chemotherapy, immunotherapy, etc.) can also be considered in combination with autophagy inhibition to develop multimodal treatment strategies to improve anti-cancer efficacy.
2. In the future, further experiments in cell response and animal models can be conducted to quantify the relationship between ROS generation and cancer cell autophagy, apoptosis and treatment effects, gain a deeper understanding of the mechanism of action of ROS, and thus optimize treatment options.
3. Although this study focused on TNBC, this treatment strategy can be extended to other types of cancer in the future, especially those with strong autophagy and drug resistance, to further verify its broad clinical applicability.

4. In the future, more types of acoustically activated materials can be developed, and nanomaterials that can be activated at lower energy can be designed to reduce possible side effects during treatment while enhancing their therapeutic efficiency.

Adv. Mater.
Pub Date  : 2024-12-01
DOI : 10.1002/adma.202413601

Yi Zheng, Tianhu Zhang, Meiqi Chang, Lili Xia, Liang Chen, Li Ding, Yu Chen, Rong Wu