A pH-sensitive nanomedicine incorporating catalase gene and photosensitizer augments photodynamic therapy and activates antitumor immunity

Immunological "cold" tumors including most triple-negative breast cancers (TNBCs) hardly respond to immunotherapy due to their extreme immunosuppressive microenvironment. Among various immunosuppressive factors, hypoxia provides a vital target for boosting antitumor immunotherapy as it plays a key role in mediating adaptive immune resistance of tumors. Here, a multifunctional nanomedicine incorporating a plasmid DNA encoding catalase gene (pDNA-cat) and photosensitizer Ce6 was developed to elicit robust immunity via photodynamic therapy (PDT) and hypoxia alleviation. The pH-sensitive sheddable coating of nanomedicine facilitated the codelivery of Ce6 and pDNA-cat into tumor cells. Under near-infrared laser irradiation, Ce6 generated cytotoxic reactive oxygen species (ROS) to induce immunogenic cell death (ICD), which promoted the maturation of dendric cells (DCs) and tumor infiltration of antitumor T cells. Meanwhile, tumor cells transfected with pDNA-cat expressed catalase to catalyze the O2 production from tumor-enriched H2O2 in situ. Tumor hypoxia relief not only augmented photodynamic therapy (PDT) known as an oxygen-consuming process but also induced strong antitumor immunity. Consequently, the multifunctional nanomedicine demonstrated strong efficacy to inhibit the tumor growth and recurrence.