Reactive A1 Astrocyte-Targeted Nucleic Acid Nanoantiepileptic Drug Downregulating Adenosine Kinase to Rescue Endogenous Antiepileptic Pathway

Resistance to traditional antiepileptic drugs is a majorchallengein chronic epilepsy treatment. MicroRNA-based gene therapy is a promisingalternative but has demonstrated limited efficacy due to poor blood-brainbarrier permeability, cellular uptake, and targeting efficiency. Adenosineis an endogenous antiseizure agent deficient in the epileptic braindue to elevated adenosine kinase (ADK) activity in reactive A1 astrocytes.We designed a nucleic acid nanoantiepileptic drug (tFNA-ADK(ASO)@AS1) based on a tetrahedral framework nucleic acid (tFNA), carryingan antisense oligonucleotide targeting ADK (ADK(ASO)) andA1 astrocyte-targeted peptide (AS1). This tFNA-ADK(ASO)@AS1construct effectively reduced brain ADK, increased brain adenosine,mitigated aberrant mossy fiber sprouting, and reduced the recurrentspontaneous epileptic spike frequency in a mouse model of chronictemporal lobe epilepsy. Further, the treatment did not induce anyneurotoxicity or major organ damage. This work provides proof-of-conceptfor a novel antiepileptic drug delivery strategy and for endogenousadenosine as a promising target for gene-based modulation.