(369e) Unlocking Intracellular Therapeutic Targets Using Bioinspired Materials

A wealth of potential therapeutic opportunities remains untapped within cells. For example, DNA delivered to the nucleus can interact with the native nuclear machinery to stimulate cellular production of essentially any protein of interest, whereas short interfering RNA (siRNA) delivered to the cytosol can initiate gene silencing (and the corresponding lack of protein production). Because of the exquisite specificity of these processes and the fundamental role for proteins in biology, nucleic acid medicines have unparalleled potential to modulate tissue regeneration and cure a wide range of devastating diseases, including cancers, cardiovascular diseases, and infectious diseases, yet no nucleic acid products are currently marketed. Meanwhile, various intracellular organelles are also the therapeutic targets for numerous small molecule medicines such as chemotherapies, but poorly controlled delivery regimens often cause severe side effects, multi-drug resistance phenotypes, and in some cases, a complete lack of efficacy.

Our group addresses challenges in therapeutic delivery by coupling principles in molecular design, molecular self-assembly, and chemical reaction kinetics with principles of cell and extracellular matrix (ECM) biology and the cell-material interface. In particular, soft materials (e.g. polymers and peptides) exhibit enormous chemical and mechanical tunability and have been self-assembled by our group and others into a versatile array of gene and drug-loaded nanostructures. We are particularly interested in developing nature-inspired approaches to harness native gene delivery and regulation mechanisms, and to actively control self-assembly vs. disassembly in gene and drug-loaded structures. We develop and use nanoscale materials to understand and probe cellular "unit ops,” with long-term applications including targeted drug delivery for prostate and breast cancer, and gene therapy for wound and tissue repair. This talk will highlight recent work employing peptide agents to enhance gene transfer efficacy in regenerative medicine.