Mitochondria‐Targeted Energy Disruptor for Augmented Mild Hyperthermia Therapy of Orthotopic Lung Cancer

Abstract Mild‐temperature photohyperthermia therapy (mild PHT) represents a promising therapeutic strategy for fighting against cancer, yet thermal resistance is a significant factor limiting its therapeutic potency. Herein, this study presents a mitochondria‐targeted energy disruptor that synergistically enhances mild PHT efficacy in orthotopic lung cancer through heat shock protein 70 (Hsp70)‐mediated thermal tolerance reversal and mitochondrial adenosine triphosphate (ATP) biosynthesis blockade. This strategy is primarily based on the mito‐siH‐SERS probes consisting of mitochondria‐targeted surface‐enhanced Raman spectroscopy (SERS) nanoparticles loaded with small‐interference RNA against Hsp70 (siHsp70). The mito‐siH‐SERS probe can trigger targeted mitochondrial damage due to the mild PHT effect under near‐infrared light irradiation. Evidently, both the released siHsp70 and photothermally induced mitochondrial dysfunction collectively downregulate the intracellular Hsp70 expression. Through disrupting the mitochondrial energy supply and reversing the thermal tolerance, this strategy achieves remarkable therapeutic performance for SERS‐guided mild PHT treatment of orthotopic lung tumors in mice. Overall, this work provides an effective strategy for restraining the mitochondrial energy supply and reducing the tumor thermal resistance for amplified cancer mild PHT.