Rational engineering of nanoplatforms with hierarchical targeting hepatic tumor and subcellular mitochondria for enhanced image-guided photodynamic therapy

The main challenge of photosensitizer in image-guided photodynamic therapy (PDT) is the balance between the high singlet oxygen yields and strong fluorescence performance, while simultaneously targeting certain types of cancer to achieve optimal effect in both imaging and therapy. Herein, a novel donor-acceptor system, engineered with silica coated quantum dots as the donor and a typical porphyrin (T790) as the acceptor, has been further integrated with hierarchical targeting strategy, which demonstrated capability of targeting both hepatic tumors and mitochondria. The prepared nanoparticles were found to exhibit high singlet oxygen generation of 0.86, bright red fluorescence, and a large Stokes shift of 285 nm. In vitro assays revealed that they accumulated within the mitochondria of malignant hepatocytes to induce apoptosis due to their high singlet oxygen generation and disrupt the mitochondrial membrane potential, thereby leveling proteins associated with apoptosis. In vivo studies with xenograft tumor model confirmed their excelllent fluorescence imaging capability and remarkable anti-tumor effects. Transcriptomic analysis further revealed the potential molecular mechanisms of donor-acceptor system in the PDT process. This work provides insights for elucidating the transcriptional regulation of image-guided photodynamic therapy and paves the way for the development of more efficient and precise treatment methods.