A ‘two-missile’ nanoplatform for targeting triple-negative breast cancer: prodrug activation and immune enhancement

Targeted cancer therapy remains a significant challenge due to the complexity of tumor microenvironments and the need for precise drug delivery systems that can overcome these obstacles. To address this challenge, a nanoparticle platform based on prodrug activation and immune enhancement for "two-missile" targeting of TNBC has been developed: Azido-HA@Cu₂O@DNA. This nanoparticle platform utilises azido hyaluronic acid (Azido-HA) as the primary carrier to enhance specificity to tumor tissues and targeting to tumor cells. The bioorthogonal reaction between the azido moiety and dibenzocyclooctyne-doxorubicin (DBCO-DOX) has been employed to improve the tumor targeting efficiency of chemotherapy is significantly enhanced, while the addition of copper ions promotes a Fenton-like reaction that induces cellular copper death. This mechanism not only spawns reactive oxygen species (ROS) for potent chemokinetic therapy but also facilitates the transition of macrophages from the M2 to the M1 phenotype, thereby bolstering anti-tumor immune responses. In addition, the platform's accompanying CRISPR/Cas9 system can reprogram tumor cells by down-regulating CD47 expression, enhancing macrophage recognition and phagocytosis activity, which in turn amplifies the efficacy of ensuing immunotherapy. The Azido-HA@Cu₂O@DNA nanoplatform demonstrates excellent biocompatibility and safety, offering a promising strategy for enhancing tumor treatment. This methodology integrates the precise activation of prodrugs, immune system modulation, and macrophage-mediated tumor eradication, offering a holistic and potent paradigm for cancer therapy.