Mitochondrial dynamics and energy metabolism interference therapy for promoting photothermal sensitization

• Published in: Journal of colloid and interface science Vol. 680; no. Pt A; pp. 429 - 440
• Main Authors: Liu, Cuimei, Cheng, Sihang, Zhou, Xue, Li, Lu, Wang, Chungang, Zhang, Lingyu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.02.2025
• Subjects: 2-deoxyglucose; adenosine triphosphate; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; carboxylation; Cell Survival - drug effects; Degradation; Drug Screening Assays, Antitumor; energy; Energy metabolism; Energy Metabolism - drug effects; face; glycolysis; heat stress; heat tolerance; homeostasis; Humans; Janus nanosheets; Mice; mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial dynamics; Mitochondrial Dynamics - drug effects; nanosheets; neoplasms; Particle Size; Photothermal Therapy; photothermotherapy; reactive oxygen species; Reactive Oxygen Species - metabolism; Sensitized photothermal therapy; starvation; Surface Properties; Targeting mitochondria; Degradation; Energy metabolism; Janus nanosheets; Targeting mitochondria; Sensitized photothermal therapy; Mitochondrial dynamics
• ISSN: 0021-9797; 1095-7103; 1095-7103
• DOI: 10.1016/j.jcis.2024.10.180

The targeting-mitochondrial degradable TPP-CBS-2DG JNSs improves antitumor effects through synergistically interfering with mitochondrial dynamics and inhibiting glycolysis, thereby improving the efficacy of photothermal therapy. [Display omitted] •TPP-CBS-2DG JNSs can disrupt mitochondrial dynamic homeostasis and inhibit energy metabolism.•TPP-CBS-2DG JNSs can radically inhibit the production of heat shock proteins, achieving superior photothermal efficacy.•This multifunctional 2D-dimensional material provides a candidate strategy for synergistic therapy targeting subcellular organelles. Photothermal therapy (PTT) is minimally invasive, precisely controlled, and therapeutically effective treatment method. However, its efficacy is limited by the overexpression of heat shock proteins (HSP), which leads to cellular thermal blockade. Targeting mitochondria with PTT can enhance anticancer efficacy, as mitochondria encode genes related to HSP and provide energy for their production. Nevertheless, mitochondrial dynamics confer resistance to damage from external stimuli. Therefore, disrupting the balance of mitochondrial dynamics is essential to impede HSP production. Herein, we synthesized degradable Cu3BiS3 (CBS) nanosheets (NSs) with one face modified by carboxylated triphenylphosphonium (TPP) to target mitochondria. This modification increases the production of exogenous reactive oxygen species (ROS) and induces the overexpression of dynamin-related protein 1 (Drp1), disrupting mitochondrial dynamic homeostasis. The other face was modified with carboxylated β-cyclodextrin (CD) to load the glycolysis inhibitor (2-deoxyglucose, 2DG), thereby reducing adenosine triphosphate (ATP) production in the extra-mitochondrial space, as glycolysis also occurs in the cytoplasm. The resulting TPP-CBS-2DG Janus NSs (JNSs) not only disrupt mitochondrial energy production, leading to cell starvation, but also inhibit HSP production. Consequently, TPP-CBS-2DG JNSs can enhance tumor thermal sensitivity in PTT, improving its efficacy. This work holds great promise for overcoming tumor heat resistance in PTT and provides a feasible method for fabricating selectively modified multifunctional NSs.