Targeting Neutrophil Hitchhiking for Drug Delivery to Block CCL5‐CCR1 and Effectively Alleviate Acute Lung Injury

ABSTRACT Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a severe respiratory condition characterized by acute, diffuse inflammatory damage to the lungs, posing a significant threat to human health. Although neutrophils and macrophages are known to play critical roles in ALI/ARDS pathogenesis, the precise cellular pathways governing their interaction remain poorly defined, and targeted therapeutics modulating these pathways are currently lacking. Here, we show that macrophages secrete CCL5 to activate CCR1 on neutrophils, thereby driving neutrophil chemotaxis toward the lungs in ALI. Mechanistically, this signaling axis operates primarily through Giα2‐dependent suppression of intracellular cAMP levels. Pharmacological inhibition of CCR1 with BX471 blocks this pathway and attenuates ALI progression. Furthermore, we developed a nanoparticle‐based delivery system encapsulating BX471 that exploits the intrinsic bone marrow‐homing property of CXCR4 high senescent neutrophils. This neutrophil‑guided strategy enables targeted drug release within the bone marrow, effectively inhibiting neutrophil egress to the lungs at the source. This approach not only significantly alleviates ALI by reducing drug dosage and administration frequency but also offers the superior safety advantage of being non‐toxic to cells and tissues. Together, our findings reveal a key cellular communication axis in ALI/ARDS and present a novel, cell‑guided therapeutic strategy for targeted intervention in inflammatory lung injury.