Resveratrol‒loaded self‒assembled tetrahedral framework nucleic acids reshape the epileptic microenvironment by regulating oxidative stress and neuroinflammation via the SIRT3/SOD2 pathway.

BACKGROUND: Epilepsy management remains a significant clinical challenge, as conventional antiseizure medications primarily mitigate symptoms without addressing the core pathological drivers, specifically the vicious cycle formed by neuroinflammation and oxidative stress. Furthermore, the therapeutic efficacy of potential neuroprotective agents is severely compromised by the blood‒brain barrier (BBB), poor stability, and insufficient accumulation at epileptic lesions. Therefore, engineering a BBB‒penetrating delivery strategy that simultaneously disrupts the vicious cycle of neuroinflammation and oxidative stress is critical for achieving disease‒modifying effects in epilepsy treatment. RESULTS: Here, we developed a biomimetic, brain‒targeting nanosystem (R‒tFNAs@PB) by anchoring resveratrol‒loaded tetrahedral framework nucleic acids (tFNAs) onto a Prussian blue (PB) core. This nanosystem effectively traversed the BBB and exhibited precise accumulation within hippocampal epileptic foci. Mechanistically, R‒tFNAs@PB acted as a dual‒function modulator. The PB core and resveratrol synergistically scavenged reactive oxygen species (ROS) and activated the SIRT3/SOD2 signaling pathway, thereby increasing the mitochondrial antioxidant capacity. This cascade effectively inhibited NLRP3 inflammasome activation and promoted the polarization of microglia from the proinflammatory M1 phenotype to the anti‒inflammatory M2 phenotype. In a mouse model of kainic acid‒induced epilepsy, the nanosystem significantly reduced neuronal damage, reduced the seizure frequency and severity, and ameliorated cognitive deficits. CONCLUSIONS: This study presents a novel nanotherapeutic strategy that integrates microenvironment remodeling with neural repair. By leveraging the specific brain‒targeting capability of tFNAs and the synergistic antioxidant properties of the core‒shell structure, R‒tFNAs@PB represent a promising approach for treating refractory epilepsy through the precise regulation of the oxidative stress‒neuroinflammation axis via the SIRT3/SOD2 pathway.