Smart Energy-Storing DNA Hydrogel for On-Demand Laser-Free Photoimmunotherapy of Melanoma

Photoimmunotherapy, which synergizes phototherapy and immunotherapy, holds significant potential for cancer treatment but demands more precise and effective strategies. Herein, we present a smart DNA hydrogel with energy-storing capabilities that responds to multiple tumor markers, enabling laser-free, on-demand photoimmunotherapy for localized melanoma treatment. The hydrogel is constructed from two single-stranded DNA chains via rolling-circle amplification, incorporating aptamers (Apt PD-1), oligonucleotides (CpG ODNs), and recognition sites for the HhaI endonuclease, enabling a controlled release of the photodynamic module. This module, composed of the AS1411 aptamer, a photosensitizer, and energy-storing persistent luminescent nanoparticles, facilitates selective tumor cell uptake and glutathione-triggered phototherapy in the absence of external irradiation, generating tumor-associated antigens for immunotherapy. Upon specific binding to T cells, Apt PD-1 blocks PD-1 receptors, promoting the release of CpG ODNs to enhance immunotherapy. In a murine melanoma model, the photoimmunotherapy system achieved a tumor inhibition rate of 73.3%. This laser-free, on-demand strategy based on the energy-storing DNA hydrogel offers a precise approach to cancer therapy and highlights the potential of DNA materials in advancing precision medicine.