Cumbersome syntheses, low loading capacities, and nucleic acid stability still limit the applicability of current non-viral vectors. Polymer systems and some emulsionbased lipid systems use techniques that can destabilize nucleic acids or struggle with phase separation of the nucleic acid. Additionally, residual catalysts and impurities from syntheses may contaminate vectors and degrade the nucleic acid therapeutic. Lipidbased carriers are common for nucleic acid delivery. Unfortunately, lipid nanoparticles (LNP) have reportedly low loading capacity, approximately 2-3 RNA strands per LNP. Of significant concern is the lack of efficient gene expression from current non-viral vectors caused by nucleic acid degradation due to physiological conditions and thermal storage conditions. The limitations of current nucleic acid therapy carriers warrant ongoing efforts to design improved formulations. Metal-organic frameworks (MOFs) emerge as a promising solution to address challenges faced by current non-viral vectors, offering gentle loading methods, high loading capacities, and the potential to protect and stabilize nucleic acids chemically and physically. MOFs are porous coordinated polymers formed from metal ions such as zirconium (IV), iron (III), and zinc (II) and organic ligands that feature multiple amine and carboxyl groups extended from alkyl backbones or ring-based structures. The self-assembled architecture of MOFs is highly porous and tunable, which has led to wide applications of MOFs in fields such as catalysis, gas absorption and separation, sensors, energy storage, water treatment, and drug delivery. Specific to drug delivery, MOFs have high drug loading capacity, biodegradability, biocompatibility, and a unique ability to deliver a variety of therapeutic modalities, including small molecules, gaseous transmitter molecules, biomolecules, and whole cell therapies. MOF-based drug loading can be achieved through surface attachment, post-synthetic pore encapsulation, one-pot coprecipitation, and biomimetic mineralization, reviewed in more detail by Lawson et al. Interestingly, Biomimetic mineralization has been demonstrated with proteins and nucleic acids, stabilizing proteins chemically and physically. To date, only a few MOF-based delivery platforms have been designed for nucleic acid delivery, briefly reviewed in Table . Early works focused on the surface loading of short interfering RNA (siRNA) onto UiO-66 and MIL-101(Fe) for multimodal therapies combating multidrug-resistant cancers. A later study completed by Hidalgo et al. studied the dependency of post-synthetic, siRNA pore encapsulation on MOF physiochemical properties through pH adjustments and ligand functionalization. Along with the successful encapsulation of siRNA, this study demonstrated the delivery of microRNA-145 (miRNA-145) and gene knockdown in colorectal cancer cells . Also using postsynthetic pore encapsulation, Peng et al. demonstrated the stabilization of singlestranded DNA (ssDNA, 11-53 nucleotides) in Ni-IRMOF-74, emphasizing the tailorable nature of MOFs with isoreticular chemistry. Interestingly, Ni-IRMOF-74 exhibited ssDNA delivery that rivaled the performance of current commercial transfection reagents in immune cells. Altogether, these studies show the success of MOFs in delivering short nucleic acid therapies via surface loading and pore encapsulation. While these encapsulation strategies work for small nucleic acids, it is acknowledged that alternative methods are better suited for larger nucleic acids such as plasmid DNA (pDNA) and mRNA. This is due to factors like their stability, physical size, and structure, which can hinder their incorporation using the abovementioned encapsulation approaches. Biomimetic mineralization and one-pot coprecipitation strategies have demonstrated successful encapsulation and delivery of large nucleic acids. These methods create a self-assembled cage around their nucleic acid cargo, engulfing large nucleic acids and protecting them from physiological conditions. 8, Poddar et al. demonstrated the biomimetic mineralization of Zeolitic Imidazole Framework-8 (ZIF-8) and delivery of a pDNA (~6.5 kilo-base pairs(kbp)) expressing a proof-of-concept enhanced Green Fluorescent Protein (eGFP) in pancreatic islet cells and human epithelial prostate cancer cells. Pushing their work further, a 9.2-kbp plasmid therapeutic was delivered as prostate cancer therapy. Coincidingly, Li et al. described the one-pot coprecipitation of pDNA with nanoscale ZIF-8 and a polycationic polymer, polyethyleneimine. Improvements in loading efficiency were demonstrated over biomimetic mineralization with comparable transfection efficiency to commercial lipidbased reagents. Interestingly, one group did report successful surface loading and delivery of a 10-kbp plasmid; however, their loading capacity was two to three-fold lower.