Engineered biomimetic exosomes for small activating RNA delivery: Low-density lipoprotein receptor-related protein-1 targeted blood-brain barrier penetration and dual therapy in intracerebral Hemorrhage.

Efficient brain-targeted gene delivery remains a formidable primary bottleneck in the clinical management of intracerebral hemorrhage (ICH). Herein, we engineered a dual-functional biomimetic nanoplatform (L57-NExos@saRNA) that synergizes active blood-brain barrier (BBB) penetration with intrinsic neuroregeneration. Guided by transcriptomic profiling, a small activating RNA (saRNA) was designed to upregulate activating transcription factor 3 (ATF3) -a critical repressor of the Toll-like receptor 4 (TLR4) neuroinflammatory cascade. To overcome formidable physiological barriers, the saRNA was condensed within neural stem cell-derived exosomes (NExos) surface-functionalized with the low-density lipoprotein receptor-related protein-1 (LRP1)-targeting peptide L57. By proactively exploiting the pathological upregulation of LRP1 on BBB-associated astrocytes following ICH, this L57-modified nanoplatform achieves highly efficient receptor-mediated transcytosis, ensuring robust and specific accumulation at the hemorrhagic lesion. Once internalized, the nanomedicine orchestrates a profound dual-therapeutic response. First, the delivered saRNA specifically reprograms microglia from a neurotoxic (M1) to a neuroprotective (M2) phenotype. This shift fundamentally rectifies maladaptive microglial-astrocyte crosstalk, subsequently driving reactive astrocytes toward an A2 protective state to deeply detoxify the inflammatory microenvironment. Concurrently, the bioactive NExos carrier itself transcends its role as a mere vehicle by activating the PI3K/Akt survival pathway, directly inhibiting neuronal apoptosis and facilitating network repair. By seamlessly converging precise BBB-targeted gene regulation with biomimetic carrier-driven repair, this versatile delivery system presents a highly translational and promising therapeutic paradigm for ICH.