An antagomiR-loaded β-peptide hydrogel promotes functional recovery in mice post-ischaemic stroke

Ischaemic stroke is a leading cause of mortality and disability, arising from interrupted cerebral blood flow and subsequent neuronal death. MicroRNAs, particularly miR-181a, have emerged as promising therapeutic targets due to their roles in regulating apoptosis and oxidative stress. While miR-181a inhibition using antagomirs can improve neuronal survival, translation to clinical practice is hampered by inefficient delivery across the blood-brain barrier and poor pharmacokinetics. Here, we developed a series of novel β-peptide hydrogels as injectable delivery systems to encapsulate and release a miR-181a antagomir in a controlled manner within the infarct region. β-peptides were synthesised with varied incorporation of β-homolysine residues to modulate electrostatic interactions with nucleic acids. The resulting hydrogels demonstrated shear-thinning and self-healing properties, stiffness values within the physiological range of brain tissue and tunable nucleic acid release profiles extending over 3 weeks. Following photothrombotic stroke in mice, intracerebral injection of antagomir-loaded hydrogel achieved precise infarct delivery and sustained presence for at least 7 days. Although infarct size reduction was modest, functional recovery, measured by improved motor coordination in the hanging wire test, was significantly enhanced in the hydrogel-antagomir group compared with controls. These findings highlight β-peptide hydrogels as promising platforms for localised, sustained delivery of nucleic acid therapeutics. This work establishes proof-of-concept for hydrogel-mediated miRNA delivery in stroke and provides a foundation for further optimisation in clinically relevant models.