Precise nanodelivery of screened compounds alleviates sepsis-associated encephalopathy by targeting microglial ANXA2.

Summary

This translational study identified microglial Annexin A2 (ANXA2) as a candidate driver of sepsis-associated encephalopathy and screened evodiamine as an ANXA2-binding compound. An Angiopep-2/phosphatidylserine-modified liposomal formulation improved brain delivery and reduced neuroinflammation, neuronal apoptosis, anxiety-like behavior, and cognitive impairment in septic mice.

Key Findings

• Integrative analysis of septic patient brain tissue identified ANXA2 as a microglia-associated candidate linked to sepsis-associated encephalopathy.
• Evodiamine was identified as an ANXA2-binding compound, and an Angiopep-2/phosphatidylserine-modified liposome was developed to improve blood-brain barrier penetration.
• The formulation improved behavior and cognition, reduced hippocampal neuroinflammation and neuronal apoptosis, and produced effects dependent on the ANXA2-binding pocket and ANXA2/NF-κB pathway.

Clinical Implications

ANXA2/NF-κB signaling and targeted nanodelivery may provide future therapeutic strategies for persistent neurological complications after sepsis. Clinical translation will require confirmation of target expression in diverse patients, optimized formulation safety, and evaluation of neurocognitive benefit in clinically relevant models.

Limitations

• The therapeutic evidence is preclinical and does not establish efficacy or safety in humans with sepsis-associated encephalopathy.
• The generalizability of ANXA2 dependence across different infection sources, pathogens, ages, and comorbidity profiles remains uncertain.

Future Directions

Future studies should validate ANXA2 as a biomarker and therapeutic target in longitudinal human cohorts, compare evodiamine with established neuroprotective agents, evaluate long-term cognition and functional recovery, and conduct pharmacokinetic and toxicology studies of the liposomal formulation.