An intelligent poly aptamer-encoded DNA nanoclew for tumor site activated mitochondria-targeted photodynamic therapy and MR imaging

Mitochondria-targeted photodynamic therapy (PDT) has emerged as one of the most promising antitumor therapies, as it significantly enhances the efficacy of photosensitizers. An efficient and biocompatible nanocarrier to deliver cationic photosensitizers (PSs) is vital for mitochondria-targeted PDT but still challenging. Herein, a poly-AS1411 aptamer DNA nanoclew (AS-AMD) synthesized via rolling circle amplification (RCA) is developed, incorporating mitochondria-targeted PSs (APNO) and paramagnetic Mn²⁺ for mitochondria-targeted PDT and magnetic resonance imaging (MRI). The AS1411 aptamer of AS-AMD has been engineered to enhance tumor targeting and cellular internalization. Paramagnetic Mn²⁺ released in the acidic tumor microenvironment promotes MRI performance of the tumor tissue and guides subsequent PDT. The released cationic APNO selectively targets the mitochondrial membrane and generates reactive oxygen species (ROS) that induce the apoptosis of 4T1 breast tumor cells. Additionally, AS-AMD exhibits effective tumor targeting in the 4T1-tumor-bearing mice model, significantly enhanced MRI performance and PDT efficacy. Therefore, this study introduces an interesting strategy to achieve efficient mitochondrial-targeted delivery of cationic PSs and provides a versatile biocompatible DNA nanoplatform for the development of nanotheranostic agents.