Abstract: Traditional methods for targeted cellular delivery have issues related to biocompatibility. High dosage of lipofectamine or coacervate would lead to cell damage that a high delivery efficiency is almost impossible. A biocompatible delivery agent is urgently needed to tackle this challenge. We recently developed a facet-based design where equimolar canonical DNA oligonucleotides self-assemble to form a nested cube linked by trapezoids, denoted as a tesseract inspired by the four-dimensional hypercube. Cryogenic electron microscopy (Cryo-EM) and atomic force microscopy (AFM) analysis revealed a fully formed tesseract structure with exceptional stiffness and a melting temperature of 84°C, significantly higher than other unmodified DNA nanostructures. The stability of tesseract allowed us to further study the efficacy of cellular delivery. Luciferase mRNA and antisense oligo were tethered onto the tesseract separately for the delivery in mouse and cellular model. The expression of luciferase was found to be superior to using coacervate in animal models. The antisense oligo on tesseract was found to be delivered into the MC3T3E1 for the knock down of MMP14 protein to enhance proliferation of bone tissue tackling the issue of osteopenia. These two examples illustrated the potential of using DNA tesseract as a versatile platform for the delivery of imaging or therapeutic agent in vivo with extraordinary stability and biocompatibility.
Funding Source: GRF (No. 17125920, 17125221) TBRS T12-201/19-R HMRF 09202246 HKU Seed Funding for Strategic Interdisciplinary Research (No. 102009959) HKU Seed Funding for Basic Research (No. 328279218) NSF (Grant no. CMMI 2323969)
