Qian Chen, Brown University

"Single-Small-Molecule Directed Assembly of Nanomaterial for Cartilage Drug Delivery and Tissue"

Cartilage is an avascular dense connective tissue that contains negatively charged extracellular matrix (ECM) with a pore size as small as 20 nm. It poses as a barrier to drug delivery and a challenge for tissue repair. To overcome this challenge, we, inspired by Watson-Crick base pair interaction, designed a class of single self-interacting small molecule JBAK, Janus-Base with Amine or Lysine (K). Under physiological conditions, JBAK forms nanotubes (NT) via homotypic interactions of hydrogen bonds and hydrophobic effects. The JBAK NT is bio-functionalized with matrilin-3, a native cartilage ECM protein. Assembly of matrilin-3 with JBAK NT not only converts scaffolding structure from nanostrings to nanobundles, but also confers pro-chondrogenesis and anti- angiogenesis properties to the matrilin-3/JBAK hybrid structure. Such bybrid scaffolding has been used for tissue engineering based growth plate cartilage fracture repair successfully. To facilitate intracellular delivery of nucleic acid, we, inspired by histone/DNA interactions in the chromosomes, assembled JBAK NTs with RNA via heterotypic interactions of lysine-mediated electric attractions and base stacking. This process encapsulates negatively charged RNA into a positively charged helical rod, which is named nanopiece (NP). NP has the potent ability to deliver nucleic acid therapeutics and diagnostics to hard-to-reach tissues such as cartilage, brain, and solid tumor. It has been demonstrated as a platform drug delivery technology for treatment of multiple diseases including chondrosarcoma, osteoarthritis, and rheumatoid arthritis.