Exploring the therapeutic potential of sγPNA-141: Pharmacodynamics and mechanistic insights during ischemic stroke recovery

MicroRNA-141-3p plays a detrimental role in the pathology of ischemic stroke, presenting a new target for stroke treatment. This study introduces and validates a novel class of peptide nucleic acid (PNA)-based miR-141-3p inhibitors known as serine gamma PNA-141 (sγPNA-141) for ischemic stroke treatment. After synthesis, physicochemical characterization, and nanoparticle encapsulation of sγPNA-141, we compared its safety and efficacy with traditional phosphorothioate- and regular PNA-based anti-miR-141-3p (PNA-141) <i>in vitro</i>, followed by detailed <i>in vivo</i> and <i>ex vivo</i> efficacy testing of sγPNA-141 for treating ischemic stroke using a mouse model. sγPNA-141 demonstrated higher affinity and specificity toward miR-141-3p, and when applied post-stroke, demonstrated decreased brain damage, enhanced neuroprotective proteins, reduced tissue atrophy, swift improvement in functional deficits, and improvement in learning and memory during long-term recovery. Overall, our data show sγPNA-141 has neuroprotective and neuro-rehabilitative effects during stroke recovery. Furthermore, we demonstrated sγPNA-141's effects are mediated by the TGF-β-SMAD2/3 pathway. In summary, the present findings suggest that sγPNA-141 could be a potentially novel and effective therapeutic modality for the treatment of ischemic stroke.