CHONDROITINASE ABC AND BDNF MRNA POLYPLEX DELIVERY SUPPORTS NEURONAL REGENERATION IN ACUTE HIPPOCAMPAL LESIONS

Acute central nervous system (CNS) injuries remain a major therapeutic challenge due to the limited regenerative capacity of neural tissue and are a significant cause of disability worldwide. Enzyme Chondroitinase ABC (ChABC), which degrades chondroitin sulfate proteoglycans in the fibrotic scar, together with Brain-Derived Neurotrophic Factor (BDNF), are promising agents to promote neuronal survival and axonal growth. Polymeric carriers may enable targeted delivery of such therapeutics to the CNS. Here, we evaluated a poly(2-oxazoline)-based polymeric carrier for drug delivery and its potential to support neuronal regeneration.
Nanoparticles were prepared via polyplex formation, and mRNA encoding BDNF was synthesized using the mMESSAGE mMACHINE T7 Ultra Kit. Adult male Wistar rats underwent bilateral intrahippocampal lesions (ibotenic acid) followed by application of ChABC and polyplexes (polymer + BDNF). Behavioral outcomes were assessed with Novel Object Recognition (NOR) and Y-maze tests. Polymer distribution after intranasal administration was visualized in 3D using lightsheet microscopy. In vitro, a fibrotic scar model was established with primary hippocampal neurons cocultured with astrocytes and fibroblasts. Immunohistochemistry was performed using confocal microscopy.
We confirmed polymer presence in the brain within hours after administration. One week post-lesion, NOR performance decreased, which was reversed by ChABC and polyplex BDNF treatment. Increased mitochondrial oxygen radicals in neurons on fibrotic scar polyplex recovered to control levels after ChABC and polyplex administration. These results suggest that polymeric delivery of BDNF, combined with enzymatic scar modulation, may support functional recovery and neuronal plasticity after CNS injury.
Work was supported by PostdokGrant APD0166.