Sprecher
Beschreibung
mRNA therapy represents a paradigm shift in therapeutics by enabling transient expression of target proteins, facilitating rapid and scalable treatment modalities with high specificity. Leveraging endogenous cellular machinery for translation, mRNA-based therapeutics bypass traditional gene therapy's integration risks and offer controlled protein production. This approach is particularly transformative for personalized medicine, enabling precise modulation of protein expression in response to pathological states. Lipid nanoparticles are the most advanced delivery vehicles for mRNA, offering high encapsulation efficiency and cellular uptake, though their potential immunogenicity and off-target delivery remain challenges. Polymer-based nanoparticles provide versatile and tunable delivery options, but face issues with biocompatibility and potential cytotoxicity. Viral vectors, while highly efficient in transduction, pose significant safety concerns due to insertional mutagenesis and immune responses, necessitating advancements in vector design for safer clinical applications. The DNA-based structural nanotechnology facilitates the design of mRNA delivery vectors with precise spatial arrangement of ligands, enabling optimal multivalent interactions akin to viral capsids, thus enhancing cellular binding and uptake efficiency. This biomimetic configuration ensures targeted delivery by precisely orienting ligands to engage specific cellular receptors, thereby improving endocytosis. The controlled spatial presentation of immunomodulatory ligands on the nanoparticle surface can mimic viral strategies to suppress untoward immune responses, reducing immunogenicity and enhancing biocompatibility. In this work, we investigate the design space of mRNA delivery vectors by integrating the protective encapsulation against nuclease degradation afforded by a lipid membrane with the precise spatial patterning and orientation of functional ligands enabled by a DNA-based nanocage, thereby creating a hybrid vector that synergizes these advantageous features. We sandwiched a model mRNA between two DNA-based half-cages bearing strategically designed ‘glue’ strands holding the mRNA in place and lipid-modified anchors for assembling the lipid membrane on top of the nanostructures. This work reports structural and functional characterization of hybrid lipid-DNA-mRNA nanostructures.
