DNA tetrahedron nanomedicine for enhanced antitumor and antimetastatic effect through the amplification of mitochondrial oxidative stress

Amplifying mitochondrial oxidative stress by elevating reactive oxygen species (ROS) and reducing glutathione (GSH) levels proved highly effective in eradicating tumor cells and inhibiting metastasis. How to significantly amplify mitochondrial oxidative stress remains a challenge due to the hypoxic microenvironment and high level of GSH in the mitochondria. Herein, we smartly fabricated a multifunctional DNA tetrahedron nanomedicine (tDNA-TPP-AuNCs-BPQDs) for intracellular enzyme activated fluorescence imaging and amplified mitochondrial oxidative stress. The apurinic/apyrimidinic site (AP site) on the cantilever of DNA tetrahedron (tDNA) could be rapidly cleaved by apurinic/apyrimidinic endonuclease 1 (APE1), allowing for in situ fluorescence imaging of APE1 with high sensitivity and specificity. Gold nanoclusters (AuNCs) could continuously convert intracellular H₂O₂ to O₂ to alleviate the hypoxic conditions and adsorb intracellular GSH, thus the photodynamic therapy (PDT) effect of black phosphorus quantum dots (BPQDs) and AuNCs triggered a ∼10-fold and ∼3-fold increase in ROS generation compared to tDNA-TPP and tDNA-TPP-BPQDs, respectively. The elevated ROS and reduced GSH led to mitochondrial oxidative stress. In addition, the photothermal therapy (PTT) effect of the BPQDs and AuNCs further amplified the mitochondrial oxidative stress, which successfully induced immunogenic cell death (ICD) process and triggered a systemic antitumor immune response. The nanomedicine could render activation of fluorescence signal and anti-tumor therapeutic activity (34-fold higher than control) in tumor, thereby achieving effective tumor growth inhibition and antimetastatic effects. STATEMENT OF SIGNIFICANCE: 1. An effective mitochondrion targeting delivery system (tDNA-TPP-AuNCs-BPQDs) was developed for enhanced antitumor and antimetastatic effect through amplifying mitochondrial oxidative stress. 2. The multifunctional nanomedicine integrates tetrahedra DNA, Au NPs, TPP, and BP quantum dots to synergistically enhance cancer therapy effect through amplified mitochondrial oxidative stress. Additionally, an AP site segment was strategically incorporated into the tDNA structure for in situ fluorescence imaging of APE1 with high sensitivity and specificity in tumor cells. 3. The elevated ROS and reduced GSH amplify mitochondrial oxidative stress to induce ICD. The relieved hypoxic tumor microenvironment and induced ICD further stimulate a systemic antitumor immune response.