Tiny pH-Resolved\nDNA Nanospheres for Cellular Pyroptosis\nor Apoptosis Regulation

The design and synthesis of nanomedicines capable of\nregulating\nprogrammed cell death patterns to enhance antitumor efficacy remain\nsignificant challenges in cancer therapy. In this study, we developed\nintelligent DNA nanospheres (NS) capable of distinguishing tiny pH\nchanges between different endosomal compartments to regulate pyroptosis\nor apoptosis. These NS are self-assembled from two multifunctional\nDNA modules, enabling tumor targeting, acid-responsive disassembly,\nand photodynamic therapy (PDT) activation. By modifying the embedded\ni-motif sequence, the NS can be activated in early endosomes (EE)\nor lysosomes (Ly), producing singlet oxygen (<sup>1</sup>O<sub>2</sub>) at specific locations under laser irradiation. Our results demonstrate\nthat EE-activated PDT induces gasdermin-E-mediated pyroptosis in tumor\ncells, enhancing antitumor efficacy and reducing systemic toxicity\ncompared to Ly-activated apoptosis. This study offers new insights\ninto the design of endosome-activated nanomedicines, advancing the\nbiomedical applications of targeted cancer therapy.