M2 macrophage-derived exosomes delivering haptoglobin and interleukin-10 plasmids for synergistic therapy of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) carries high mortality and disability rates, driven not only by the initial bleeding but also by secondary neurotoxicity from blood derived components such as hemoglobin. An effective strategy during the subacute phase must therefore address both hematoma clearance and neuroinflammation. To achieve this dual action therapy, we engineered a novel nanoplatform (M2-exo@HI) by encapsulating a plasmid co-expressing haptoglobin (Hp) and interleukin-10 (IL-10) within M2 macrophage-derived exosomes. Leveraging the innate inflammatory homing of macrophage exosomes, M2 exo@HI delivers the HI plasmid to the ICH site, where it is primarily internalized by M1 microglia. The expressed Hp binds hemoglobin, reducing neurotoxicity and exert neuroprotective effects. Simultaneously, IL-10 polarizes M1 microglia to the neuroprotective M2 phenotype, thereby removing hematoma and alleviating neuroinflammation via anti-inflammatory cytokine production. Consequently, M2-exo@HI significantly reduced hematoma volume, improved long-term neurological function, and enhanced blood-brain barrier (BBB) repair. Transcriptome analysis further elucidated the genetic mechanisms underlying this synergistic effect. This work presents a promising co-delivery strategy for enhancing hemorrhagic stroke therapy.