Acid‐Responsive Nanomotors Regulate the Crosstalk between Neutrophils Infiltration and Acidosis for the Precise Targeted Treatment of Ischemic Stroke

Abstract Ischemic stroke remains a major global medical challenge. Despite advancements in thrombolytic therapies, a significant proportion of patients continue to face poor/unfavorable outcomes, primarily attributable to the detrimental effects of neuroinflammation and metabolic dysfunction. This study investigates the complex interactions between neutrophil infiltration and acidosis in ischemic stroke, aiming to elucidate the mechanism in regulating neurological function. Acid‐responsive, oxygen‐driven nanomotors are engineered, designated as MDd‐ptNPs composed of a shell utilizing a hybrid membrane (MD) integrating macrophage membrane and acid‐sensitive 1,2‐dioleoyl‐sn‐glycero‐3‐phosphoethanolamine (DOPE), and a core containing platinum nanoparticles (ptNPs) and deoxyribonuclease I (Dnase I). Through macrophage membrane‐mediated inflammatory chemotaxis and DOPE's pH sensitivity, this approach enables targeted drug delivery to ischemic lesions. MDd‐ptNPs utilize interaction between C‐C motif ligand 2 (CCL2) and C‐C motif chemokine receptor 2 (CCR2) decoys, while releasing Dnase I to reduce neutrophils and neutrophilic extracellular traps. It alleviates mitochondrial dysfunction caused by neuroinflammation and produces a lot of oxygen for facilitating deeper drug penetration, thereby reducing neuronal acidosis and suppressing neutrophil infiltration. Overall, MDd‐ptNPs significantly alleviates ischemic brain injury and improves post‐stroke depression by modulating the crosstalk between neutrophils and acidosis.