A quest for cytocompatible metal organic frameworks in non-viral gene therapy: Relevance of zeolitic imidazolate framework-8

Metal-organic frameworks (MOFs) are an emerging group of nanomaterials for successful biomedical applications in gene therapy. The most commonly biocompatible MOFs are zinc-based ZIFs, zirconium-based UiOs, and iron-based MILs. However, despite increasing applications, a comparative study to underscore the critical factors for determining effective gene delivery by such MOFs is lacking. Herein, we evaluate the potential of UiO-66 and MIL-88B and ZIF-8 for gene therapeutics delivery; revealing the comparative importance of ZIF-8. Cytotoxicity assays proved insufficient for selecting the ideal gene delivery MOF vehicle. Synthesis conditions such as ability of the MOF scaffold to envelop the gene during in-situ synthesis, post-treatment such as washing, and gene loading efficiency proved to be the critical factors in determining the favourable MOF from the material selection perspective. Rapid in-situ synthesis under physiological conditions, successful gene loading, and low concentration requirements favour ZIF MOFs as gene delivery vehicles. Impact on cellular physiology, metabolism, and architecture revealed neutrality of the delivery system; and relative effects on pro-inflammatory and anti-inflammatory cytokines suggest immunomodulatory impact.