L57-targeted NExos@saRNA system penetrates BBB, reprograms microglia, and activates PI3K/Akt for dual intracerebral hemorrhage therapy

Efficient brain-targeted gene delivery remains a significant challenge in managing intracerebral hemorrhage (ICH), a devastating stroke subtype. Current treatments often fall short in addressing both acute injury and long-term neuroinflammation. The blood-brain barrier (BBB) poses a formidable obstacle, limiting therapeutic access to the brain parenchyma. This study explores a novel biomimetic exosome-based strategy to overcome the BBB and deliver therapeutic cargo, leveraging specific receptor targeting to enhance delivery and achieve a dual neuroprotective effect.

Researchers engineered a dual-functional biomimetic nanoplatform (L57-NExos@saRNA) designed for active blood-brain barrier (BBB) penetration and neuroregeneration. This system encapsulates a small activating RNA (saRNA) within neural stem cell-derived exosomes (NExos). The saRNA was designed via transcriptomic profiling to upregulate activating transcription factor 3 (ATF3), a key repressor of the Toll-like receptor 4 (TLR4) neuroinflammatory cascade. The NExos surface was functionalized with the L57 peptide, which specifically targets the low-density lipoprotein receptor-related protein-1 (LRP1) to exploit its pathological upregulation on BBB-associated astrocytes following ICH, facilitating receptor-mediated transcytosis and targeted accumulation at the hemorrhagic lesion.

The L57-NExos@saRNA nanoplatform achieved highly efficient receptor-mediated transcytosis, ensuring robust and specific accumulation at the hemorrhagic lesion by proactively exploiting the pathological upregulation of LRP1 on BBB-associated astrocytes following intracerebral hemorrhage (ICH). Once internalized, the delivered saRNA specifically reprogrammed microglia from a neurotoxic (M1) to a neuroprotective (M2) phenotype. This critical shift fundamentally rectified maladaptive microglial-astrocyte crosstalk. Subsequently, this drove reactive astrocytes toward an A2 protective state, deeply detoxifying the inflammatory microenvironment. Concurrently, the bioactive NExos carrier itself transcended its role as a mere vehicle, activating the PI3K/Akt survival pathway. This activation directly inhibited neuronal apoptosis and facilitated network repair. > By seamlessly converging precise BBB-targeted gene regulation with biomimetic carrier-driven repair, this versatile delivery system orchestrated a profound dual-therapeutic response.