Multi-responsive nanococktails with programmable targeting capacity for imaging-guided mitochondrial phototherapy combined with chemotherapy

The integration of multimodal functions into one nanoplatform holds great promise for enhancing anticancer drug action and mitigating adverse effects. Herein, we prepared hyaluronic acid-functionalized regenerated silk fibroin-based nanoparticles (NPs) loading with photosensitizer (NIR770) and doxorubicin (DOX). The resultant HNDNPs had a desirable diameter of 161.0 nm and a negative zeta-potential of -30.5 mV. Interestingly, they showed excellent responses when triggered with various stimuli (acidity, reactive oxygen species, glutathione, hyaluronidase, or hyperthermia). Cell experiments revealed that HNDNPs could be specifically internalized by A549 cells, and efficiently released the payloads into the cytoplasm. Moreover, NIR770 was preferentially retained in mitochondria due to its lipophilic and cationic properties, which exhibited highly efficient photothermal therapy and photodynamic therapy upon near infrared (NIR) irradiation. Meanwhile, DOX molecules were mainly accumulated in the nucleus. Intravenous injection of HNDNPs into mice followed by NIR irradiation provided excellent multimodal imaging (NIR, photothermal, and photoacoustic imaging), almost eliminated the entire tumor, and greatly prolonged mice survival time with no side effects. Our study demonstrates that this HNDNP, which integrates the functions of tumor targeting, on-demand drug release, multimodal imaging, mitochondrial phototherapy, and chemotherapy, can be exploited as a promising nanococktail for imaging-guided synergistic treatment of cancer.