A Photosensitizer-Intercalated Programmable DNA System for Enhanced Photoimmunotherapy via Tumor Microenvironment Remodeling.

Photoimmunotherapy (PIT) has emerged as a minimally invasive therapeutic modality for cancer, offering high spatial precision and favorable therapeutic outcomes. However, the aggregation-caused quenching (ACQ) of photosensitizers and the hypoxic tumor microenvironment (TME) limit its overall efficacy. Herein, a DNA tetrahedron-based nanoplatform (HPTM) functionalized with hypoxia-inducible factor-1α antisense oligonucleotide (HIF-1α ASO) and PD-L1 aptamers was engineered to load TMPyP for enhanced tumor PIT. The intercalation of TMPyP within the DNA framework effectively prevented photosensitizer aggregation, thus improving reactive oxygen species (ROS) production and photodynamic therapy (PDT) efficacy. Furthermore, the aptamer-functionalized structure facilitated tumor targeting and blocked the PD-1/PD-L1 immune checkpoint on the cell surface. Concurrently, the intracellular delivery of HIF-1α ASO downregulated endogenous PD-L1 expression by disrupting the HIF-1α/PD-L1 signaling axis. This collaborative endogenous and exogenous strategy effectively remodeled the immunosuppressive TME. The downregulation of HIF-1α also alleviated the hypoxic microenvironment, further supporting PDT performance. Upon irradiation, HPTM triggered immune activation via PDT-induced immunogenic cell death (ICD) and promoted long-term immunological memory. Overall, this multifunctional DNA-programmed nanoplatform provides efficient photosensitizer loading and addresses the immune imbalance associated with PDT, offering a promising strategy for cancer PIT.