A Monocyte‐Targeted Nanoplatform for Phagocytosis Activation and Ferroptosis Inhibition in Intracerebral Hemorrhage

ABSTRACT Intracerebral hemorrhage (ICH) is a highly fatal subtype of stroke characterized by vascular rupture and hematoma formation, leading to both primary mechanical damage and secondary neuroinflammatory injury. While both microglia and infiltrating monocytes contribute to hematoma clearance, their distinct roles and therapeutic potential remain unclear. Moreover, the erythrophagocytic process is tightly constrained by the CD47–SIRPα signaling axis, which impairs effective resolution. Through integrated multi‐omics analysis, single‐cell RNA sequencing, and cross‐species validation, we identified that monocyte‐derived macrophages (MDMs)—not resident microglia—are the predominant phagocytes in the ICH microenvironment, exhibiting superior hematoma clearance capacity. However, excessive red blood cell engulfment induces ferroptosis in these cells, thereby disrupting tissue repair. To address these challenges, we engineered a multifunctional nanoparticle system, mPDA@DFO‐CpG‐N1, incorporating: (1) a high‐affinity monocyte‐targeting aptamer (N1) for selective delivery; (2) a TLR9 agonist (CpG) that bypasses CD47‐mediated inhibition by reprogramming monocytes energy metabolism to enhance phagocytic function; and (3) the iron chelator deferoxamine (DFO) to mitigate ferroptosis. The system utilizes endogenous monocyte chemotaxis for hematoma targeting and pH‐sensitive release for spatiotemporal precision. In vivo studies in a murine ICH model demonstrated that mPDA@DFO‐CpG‐N1 achieved a 3.2‐fold increase in lesion site accumulation, markedly improved hematoma clearance, suppressed monocytes ferroptosis, and significantly restored neurological function. This work reveals the pivotal role of MDMs in ICH resolution and presents a closed‐loop, multimodal therapeutic strategy integrating targeted delivery, immune modulation, and cell fate regulation for effective treatment of cerebral hemorrhage.