Circulating monocyte differentiation-activated nanoprodrugs for reprogramming macrophage immunity in atherosclerotic plaques

Atherosclerosis (AS) is characterized by the differentiation of monocytes and macrophages within AS plaques, coupled with the dysregulation of the immune microenvironment. Therefore, therapies targeting the immune microenvironment within plaques represent a promising strategy for AS treatment. However, the delivery efficiency of nanomedicine systems targeting plaques remains unsatisfactory, inevitably leading to off-target effects and premature leakage of active payloads. Based on the distinctive rise in intracellular reactive oxygen species (ROS) levels following differentiation of circulating monocytes within plaques, we designed a nano-prodrug system for spatiotemporally controllable activation of drug potency. We initially developed an inactive prodrug molecule (denoted as Citopril) with specific reactivity to ROS, and then Citopril was assembled into nanomicelles (denoted as Citop-NMs). After intravenous injection, "Trojan horse" Citop-NMs, facilitated by the polyethylene glycol (PEG) coating, can hitchhike into circulating monocytes. Moreover, Citop-NMs loaded in monocytes can efficiently accumulate within plaques via the inflammatory recruitment property of monocytes, thus achieving spatially targeted distribution. Upon the differentiation of monocyte vehicles, the elevated intracellular ROS level can trigger the temporal drug potency activation of the loaded Citopril. Treatment evaluation in an AS murine model demonstrates that Citop-NMs alleviate plaque burden without eliciting adverse reactions. Analysis of aortic macrophage phenotype unveils that Citop-NMs can regulate macrophage immunity in the lesions. The circulating monocyte differentiation-activated nanoprodrugs not only achieve targeted delivery of therapeutics to pathological sites but also effectively avoid nonspecific activation of off-target drugs in non-pathological regions. This spatiotemporally controllable strategy offers a novel approach for clinical precision medicine.