Sono-triggered endoplasmic reticulum-targeted ROS burst silencing CD300ld to alleviate polymorphonuclear myeloid-derived suppressor cells for breast cancer treatment

Immunogenic cell death (ICD) significantly boosts anti-tumor immunotherapy effectiveness; however, the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), driven by factors such as adenosine accumulation and oxygen depletion during ICD, impairs the overall therapeutic outcome as well as facilitates tumor development and metastasis. Recent studies identify CD300ld as a key regulator of PMN-MDSCs recruitment, making it a promising immunotherapeutic target. Here, an innovative strategy is developed to eminently amplify ICD while alleviating PMN-MDSC infiltration upon ultrasound (US) stimulation. A modified generation 5 (G5) poly(amidoamine) dendrimer (G5PBA) was employed to encapsulate hematoporphyrin (GH)-a widely used organic sonosensitizer-and modified the complex with pardaxin peptides (Par) to achieve precise endoplasmic reticulum (ER) targeting, and adsorbed the negatively charged siCD300ld (PGH@siRNA). Under US irradiation, PGH@siRNA precisely accumulates at ER to induce localized reactive oxygen species (ROS) bursts, and effectively silence CD300ld, thereby amplifying endoplasmic reticulum stress (ERS)-mediated ICD and reducing PMN-MDSCs infiltration to reshape the tumor microenvironment. This systematic preclinical evaluations demonstrated enhanced immune activation, suppressed metastasis, and improved therapeutic outcomes. This study introduces a sono-responsive synergistic strategy integrating ER-targeted sonodynamic therapy with gene silencing, offering a novel paradigm for targeting PMN-MDSCs and enhancing triple-negative breast cancer (TNBC) immunotherapy.