DNA Nanocage-Mediated Aspirin Delivery Mitigates Excitotoxicity and Promotes Neuroprotection in Ischemic Stroke-Induced Zebrafish

Oxidative stress, apoptosis, excitotoxicity, and compromised neuronal function are the hallmarks of ischaemic stroke, a major cause of neurological impairment. Because of their controlled-release properties and biocompatibility, DNA tetrahedron nanostructures (TD) offer a viable platform for targeted drug delivery. In this work, we used a zebrafish larval model of ischaemic stroke to assess the neuroprotective potential of TD-mediated aspirin administration and investigated the TD:Aspirin complexation modes using molecular dynamics (MD) simulations. In addition to morphological abnormalities, elevated reactive oxygen species (ROS), thrombus formation, intracellular calcium accumulation, and dysregulated expression of neuroprotective and apoptotic genes, stroke induction resulted in significant behavioural deficits, including decreased locomotor activity, increased latency, and erratic swimming. Treatment with TD:Aspirin, especially at a 1:100 ratio, markedly improved locomotor behaviour, restored production of BDNF, GDNF, MBP, -tubulin, GRIN2B, SLC8A, NOS1, and caspases, normalised heart rate, lowered ROS generation and apoptosis, and decreased thrombus and calcium deposition. TD:Aspirin showed better efficacy than free Aspirin and TD-only groups, perhaps as a result of improved stability, bioavailability, and sustained release. These results demonstrate the potential of drug delivery via DNA nanocages as a novel therapeutic approach for ischaemic stroke, offering neuroprotection, functional recovery, and neuronal homeostasis restoration. TOC GraphicDNA Nanocage-Mediated Aspirin Delivery Mitigates Excitotoxicity and Promotes Neuroprotection in Ischemic Stroke-Induced Zebrafish O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/696221v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@18dd327org.highwire.dtl.DTLVardef@21b8b4org.highwire.dtl.DTLVardef@1e53283org.highwire.dtl.DTLVardef@5771e6_HPS_FORMAT_FIGEXP M_FIG C_FIG