As a major late complication of diabetes, diabetic peripheral
neuropathy
(DPN) is the primary reason for amputation. Nevertheless, there are
no wonder drugs available. Regulating dysfunctional mitochondria is
a key therapeutic target for DPN. Resveratrol (RSV) is widely proven
to guard mitochondria, yet the unsatisfactory bioavailability restricts
its clinical application. Tetrahedral framework nucleic acids (tFNAs)
are promising carriers due to their excellent cell entrance efficiency,
biological safety, and structure editability. Here, RSV was intercalated
into tFNAs to form the tFNAs-RSV complexes. tFNAs-RSV achieved enhanced
stability, bioavailability, and biocompatibility compared with tFNAs
and RSV alone. With its treatment, reactive oxygen species (ROS) production
was minimized and reductases were activated in an in vitro model of DPN. Besides, respiratory function and adenosine triphosphate
(ATP) production were enhanced. tFNAs-RSV also exhibited favorable
therapeutic effects on sensory dysfunction, neurovascular deterioration,
demyelination, and neuroapoptosis in DPN mice. Metabolomics analysis
revealed that redox regulation and energy metabolism were two principal
mechanisms that were impacted during the process. Comprehensive inspections
indicated that tFNAs-RSV inhibited nitrosation and oxidation and activated
reductase and respiratory chain. In sum, tFNAs-RSV served as a mitochondrial
nanoguard (mito-guard), representing a viable drilling target for
clinical drug development of DPN.