Computation-aided Design of Rod-Shaped Janus Base Nanopieces for Improved Tissue Penetration and Therapeutics Delivery

Abstract

Despite the development of various drug delivery technologies, there remains a significant need for vehicles that can improve targeting and biodistribution in hard-to-penetrate tissues. Some solid tumors, for example, are particularly challenging to penetrate due to their dense extracellular matrix (ECM). In this study, we have formulated a new family of rod-shaped delivery vehicles named Janus base nanopieces (Rod JBNps), which are more slender than conventional spherical nanoparticles, such as lipid nanoparticles (LNPs). These JBNp nanorods are formed by bundles of DNA-inspired Janus base nanotubes (JBNts) with intercalated delivery cargoes. To develop this novel family of delivery vehicles, we employed a computation-aided design (CAD) methodology that includes molecular dynamics and response surface methodology. This approach precisely and efficiently guides experimental designs. Using an ovarian cancer model, we demonstrated that JBNps markedly improve penetration into the dense ECM of solid tumors, leading to better treatment outcomes compared to FDA-approved spherical LNP delivery. This study not only successfully developed a rod-shaped delivery vehicle for improved tissue penetration but also established a CAD methodology to effectively guide material design.

In-Space Fabrication of Janus Base Nano-Matrix for Improved Assembly and Bioactivities

“…These JBNs consist of small molecules mimicking DNA base pairs, self-assembled into nanotubes through hydrogen bonding and base stacking. The architecture of JBNs relies on non-covalent interactions among tens of thousands of Janus base units, each with a molecular weight below 400 Da 4,5 . These JBNs assemble via a biomimetic process at ambient temperature with minimal equipment requirements without the need for catalyst nor crosslinker during JBN formation.…”