Hypoxia-Adapted Self-Programming Exosome Nanoplatform for Ultrasound-Activated Sonodynamic Immunotherapy via STING Signaling

Tumor microenvironment-responsive nanoplatforms that integrate therapeutic and immunomodulatory functions offer a promising strategy for effective cancer treatment. Herein, we report a self-programming, hypoxia-adapted mesenchymal stem cell-derived exosome nanoplatform (H-MSC-EXO) coloaded with protoporphyrin IX (PpIX), perfluoro- n -pentane (PFP), and cyclic GMP-AMP (cGAMP) for ultrasound-activated synergistic breast cancer immunotherapy. The hypoxia-conditioned exosomal membrane enhances tumor tropism and enables adaptive responsiveness within the tumor microenvironment. Upon ultrasound (US) stimulation, PFP undergoes acoustic droplet vaporization, amplifying cavitation effects and promoting sonodynamic activity, while PpIX generates reactive oxygen species. Concurrently, cGAMP activates STING signaling, initiating innate immune responses.The system exhibits stimuli-responsive (“self-programming”) behavior, whereby hypoxic tumor microenvironment cues and ultrasound stimulation synergistically regulate therapeutic activation and immune signaling. The engineered nanovesicles demonstrate improved stability, efficient cellular uptake, and enhanced intracellular delivery compared to free cGAMP. Ultrasound irradiation significantly enhances therapeutic efficacy, achieving ∼90% cGAMP release within 24 h compared to ∼65% without stimulation, leading to tumor cell destruction, immunogenic cell death, and the release of damage-associated molecular patterns, thereby promoting dendritic cell activation and T-cell-mediated immune responses. In vivo studies demonstrate significant tumor growth inhibition without observable systemic toxicity. Collectively, this work establishes a stimuli-responsive exosome-based nanoplatform that integrates ultrasound-triggered sonodynamic therapy with STING-mediated immunomodulation for effective breast cancer treatment.