A Programmed Streptavidin-Condensed Bifunctional Nucleic Acid Nanoplatform Breaking the Vicious Cycle for Traumatic Brain Injury Therapy

A pivotal hurdle in traumatic brain injury (TBI) therapy is the self-perpetuating cycle between neuroinflammation and oxidative stress. Concurrent targeting of both pathways offers a promising strategy to overcome the key limitation in current therapy. Herein, a programmed streptavidin-condensed bifunctional nucleic acid nanoplatform (DZ-G4/H NPs) was developed via rolling circle amplification (RCA) to integrate numerous C1qa-cleaving DNAzymes with the peroxidase-like G-quadruplex/hemin (G4/H) complex. The platform ingeniously enhances the stability and drug-loading capacity of nucleic acid structures, enabling improved therapeutic efficacy through disruption of the self-perpetuating inflammation-oxidative stress cycle, which is superior to individual monotherapies. Consequently, it alleviated key pathophysiological hallmarks such as brain edema and cerebral blood flow (CBF) deficits, promoted holistic recovery of motor and cognitive functions, and ultimately improved survival in TBI mice. Beyond its promising application in TBI therapy that consolidates multiple therapeutic advantages, this nanostrategy offers a versatile method for streamlined programmed assembly of multifunctional modules, thereby providing an adaptable technical platform for the design and development of multifunctional nucleic acid drugs.