Application and Research Progress of Nucleic Acid-Based Drug Delivery Systems in the Treatment of Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is a devastating stroke subtype associated with high mortality and neurological disability, yet effective treatment remains constrained by the complex mechanisms of secondary brain injury and limited blood–brain barrier (BBB) permeability. In this context, Nucleic Acid-Based Drug Delivery Systems (NADDS) offer a promising strategy by enabling precise gene regulation and targeted modulation of disease-associated pathways. However, a systematic framework linking nucleic acid modalities, carrier design, disease stage and translational feasibility in ICH remains lacking. This review first summarizes the therapeutic mechanisms and delivery requirements of representative nucleic acid drugs, including siRNA, miRNA, antisense oligonucleotides and mRNA, for modulating neuroinflammation, oxidative stress and neurological repair after ICH. It then focuses on three major NADDS—lipid nanoparticles, exosome-based delivery systems and DNA nanomaterial-based delivery systems—highlighting their structural characteristics, design principles, cargo loading strategies, delivery mechanisms, advantages, limitations and recent applications in ICH. The major challenges encountered during NADDS-based treatment of ICH, including dynamic BBB permeability, carrier selection, insufficient loading efficiency, biosafety concerns, manufacturing scalability and patient heterogeneity, are discussed. By integrating these advances, this review clarifies the therapeutic potential of these three platforms and provides a foundation for developing safer, more efficient, and clinically translatable nucleic acid therapies for ICH.