Project Abstract Over the past decade, optogenetics has increasingly become an important technology for spatiotemporal control of neural activity, cardio functions, muscle cell activity, protein-protein interaction, and disease applications, through the genetically encoded light-activated proteins. However, there are still two major challenges of this technology: 1.the delivery of light to into deep body areas such as brain or heart generally requires the optical fiber implantation which could result in damage of cells and tissue. 2. Gene expression requires viral transduction, which suffer from a number of limitations such as the host immune response, the stability expressed proteins over time, the limitations on maximum gene size and the lack of economic scalability for manufacture. To address the first challenge, we recently developed a technology named ‘sono-optogenetics’ to convert focused ultrasound (FUS) to light for non-invasive optogenetics. The nanoparticles are injected into the circulating blood so that neither craniotomy nor intracranial implantation is required for achieving optogenetics. However, these inorganic nanoparticles are generally difficult to be modified to emit different colors of light for multiplex optogenetic control and are not biodegradable after accumulating in the animal livers after use, causing long-term safety concerns. Therefore, the goal of this proposal and the focus of my research lab, is to tackle the remaining challenges for optogenetics through designing organic nanomaterials, including hydrogen-bonded organic frameworks nanoparticles, chemical assembly of DNA plasmids and cationic polymer delivery agents. Specifically, we are planning to 1) design biodegradable nanoparticles to convert ultrasound to light for multi-colored sono- optogenetics. 2) improve the delivery of plasmid DNAs through nucleopore through covalent chemical assembly strategies and 3) design advanced cationic polymers for improving endosome escape, cellular uptake and diffusivity through extracellular space in non-viral gene delivery. The work will also enhance our understanding the transport and interaction of organic nanoparticles in cells. As a result, I believe that the proposed works is well suited for the NIH R35 Maximizing Investigators’ Research Award.