An Aged Tree with a New Bloom: A Simple Spatiotemporal\nProgramming Strategy Enables Carbon Dot Photosensitizers to Regulate\nCell Pyroptosis for Enhanced Tumor Photodynamic-Immunotherapy

Pyroptosis\ninduced by photodynamic therapy (PDT) is a promising\nfield in both PDT and immunotherapy for tumors. However, effectively\ninducing tumor cell pyroptosis while triggering a strong immune response\nusing current photosensitizers remains challenging. Herein, the developed\npositively charged carbon dots (PCDs) nanoPSs were utilized to modulate\ntumor cell pyroptosis for the first time through a simple spatiotemporal\nprogramming strategy. Briefly, PCDs enabled precisely time-dependent\ntargeting of the cell membrane or lysosome. Upon light irradiation, <i>in vitro</i> studies revealed that lysosome-targeted PDT primarily\ninduced apoptosis, while membrane-targeted PDT triggered pyroptosis,\nresulting in enhanced PDT efficacy and robust activation of the immune\nresponse. Conclusively, <i>in vivo</i> studies demonstrated\nthat PCDs could serve as a novel pyroptosis nanotuner for enhanced\nphotodynamic-immunotherapy, thereby simultaneously eliminating primary\ntumors and inhibiting distant tumor growth and metastases. This spatiotemporal\nprogramming strategy unprecedentedly offers a rejuvenation of aged\nPSs and expands the biomedical use of CDs in immunotherapy.