Ultrasound Responsive Mn/Se-Nanozyme as PANoptosis Initiators for Bladder Cancer Immunotherapy.

Bladder cancer is a major global health challenge with high recurrence and mortality. Despite advances in surgery and chemotherapy, immune checkpoint inhibitors (ICIs) have limited effectiveness due to poor immune infiltration and inadequate responses. To address these issues, we developed an ultrasound-responsive Mn/Se-NE@FCS nanozyme (NE) that activates both STING signaling and PANoptosis, a novel multi-pathway cell death mechanism involving apoptosis, necroptosis, and pyroptosis. This dual-action system enhances ROS production, mitochondrial dysfunction, and immunogenic cell death (ICD) in tumors, promoting dendritic cell (DC) maturation, CD8 T-cell infiltration, and memory T-cell expansion. The Mn/Se-NE@FCS nanozyme showed superior tumor control and synergized with PD-1 blockade in murine bladder cancer models. Histological and flow cytometry analyses confirmed that the treatment remodels the tumor microenvironment, driving immune activation and T-cell priming. This strategy offers a promising nanoimmunotherapy approach for bladder cancer, using ultrasound-triggered activation to induce multi-pathway tumor cell death and stimulate long-lasting systemic immunity.