Extracellular matrix (ECM) in a vertebrate tissue serves not only structural functions but also as a barrier to interstitial molecular transport. Such barrier function protects internal tissues from foreign substances, but poses a challenge for drug delivery. It is especially challenging to deliver negatively-charged nucleic acid into avascular, dense, and negatively-charged matrix in hard-to-reach tissues including joint cartilage, solid tumors, and brain through the blood brain barrier. One approach is to make the delivery vehicle small enough to infiltrate the ECM pores in the sub-100 nm range. However, it cannot solve the drug delivery problem completely since it gets out the tissue easily through interstitial fluid transport. Using a synthetic biology approach, our laboratory developed a biomimetic small molecule named JBAK, Janus Base with Amine and Lysine (K). The Janus-Base units mimic DNA base pairs, which interact with each other through the Watson-Crick hydrogen bond to form a non-covalent nanotube. The positively charged lysine on the surface of the nanotube interacts with nucleic acid mimicking lysine mediated DNA-protein interactions in the chromosome. After ultrasound processing, such nucleic acid and JBAK non-covalent assembly termed Nanopiece is capable of infiltrating ECM and delivering nucleic acid cargo intracellularly. Furthermore, the Nanopiece delivery vehicle has prolonged half-life in a tissue due to its lysine-mediated interaction with ECM, turning its barrier function to carrier of delivery vehicles. Using the Nanopieces platform technology, we can achieve highly efficient intracellular delivery for nucleic acid based therapeutics and diagnostics. Its efficacy has been demonstrated in preclinical animal models of multiple diseases including cancer, osteoarthritis, and rheumatoid arthritis.
Extracellular matrix (ECM) in a vertebrate tissue serves not only structural functions but also as a barrier to interstitial molecular transport. Such barrier function protects internal tissues from foreign substances, but poses a challenge for drug delivery. It is especially challenging to deliver negatively-charged nucleic acid into avascular, dense, and negatively-charged matrix in hard-to-reach tissues including joint cartilage, solid tumors, and brain through the blood brain barrier. One approach is to make the delivery vehicle small enough to infiltrate the ECM pores in the sub-100 nm range. However, it cannot solve the drug delivery problem completely since it gets out the tissue easily through interstitial fluid transport. Using a synthetic biology approach, our laboratory developed a biomimetic small molecule named JBAK, Janus Base with Amine and Lysine (K). The Janus-Base units mimic DNA base pairs, which interact with each other through the Watson-Crick hydrogen bond to form a non-covalent nanotube. The positively charged lysine on the surface of the nanotube interacts with nucleic acid mimicking lysine mediated DNA-protein interactions in the chromosome. After ultrasound processing, such nucleic acid and JBAK non-covalent assembly termed Nanopiece is capable of infiltrating ECM and delivering nucleic acid cargo intracellularly. Furthermore, the Nanopiece delivery vehicle has prolonged half-life in a tissue due to its lysine-mediated interaction with ECM, turning its barrier function to carrier of delivery vehicles. Using the Nanopieces platform technology, we can achieve highly efficient intracellular delivery for nucleic acid based therapeutics and diagnostics. Its efficacy has been demonstrated in pre-clinical animal models of multiple diseases including cancer, osteoarthritis, and rheumatoid arthritis.