CAREER: Rational Design of Phase-Changing Nanomaterials for Spatiotemporal Protein Delivery

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Non-Technical AbstractThis project will develop ultrasound-sensitive nanomaterials that can be acoustically activated to deliver otherwise-impermeable biomolecules into cells with high precision. This is achieved through the rational design of fluorous phase-changing nanoparticles (PCNs), which undergo liquid-gas phase transitions in response to acoustic stimuli. While PCNs have enjoyed success as ultrasound imaging agents, their translation into drug delivery devices has been impeded by poor cargo loading and variable biologic outcomes. Building upon prior seminal work, this project will open new opportunities in the rational design of PCNs by understanding the interdependence of particle composition and tissue mechanics on their acoustic activation, and optimize the loading and delivery of biologic cargo. These objectives will be accomplished through three aims: (1) Prepare bio-inspired PCNs and identify how physical and chemical properties impacts their ultrasound activation; (2) Demonstrate successful dispersion of proteins into the liquid interior of fluorous PCNs and assess delivery under ultrasound; (3) Pair biophysical cell-based experiments with computational models of membrane mechanics to advance a more comprehensive mechanism for PCN-mediated cell permeabilization. Success of this work will enable the design of PCNs with well controlled acoustic biophysics, yielding new biochemical tools that can be used to probe and manipulate cells within complex tissue microenvironments with high precision. Research findings from this project will be integrated with outreach activities to incorporate principles of biomaterial design and biophysics into K-12 education. Educational objectives include: (1) Examine the effect of integrating high-school students with undergraduate engineering design teams on recruitment and persistence in STEM education; and (2) Develop and implement an Ultrasound Olympics program that will provide transformative hands-on experiences to K-12 students in nanotechnology and bioacoustics. Leveraging an integrated research and outreach program, supported through rigorous and routine assessment, this project will advance new bio-nanotechnologies and improve student retention in emerging STEM fields. Technical AbstractThe goal of this CAREER award is to develop a framework for the rational design of fluorous phase-changing nanoparticles (PCNs) that can be vaporized by ultrasound to afford transmembrane delivery of biomolecules into cells with spatial and temporal precision. Although PCNs have enjoyed success as ultrasound contrast agents, their translation into clinically useful delivery vehicles has yet to be realized. This is a consequence of two key gaps in knowledge that include: (1) a lack of well-defined structure-activity relationships defining how PCN physicochemical properties regulate their phase-changing behavior; and (2) an incomplete mechanistic understanding of how local tissue mechanics impacts PCN biophysics. Using template-driven peptide assembly, this project will prepare programmable PCNs to elucidate the influence of particle surface tension and size on their acoustic activation, as well as identify conditions that allow protein cargo to be loaded into, and delivered from, the fluorous liquid particle core. In parallel, this project will identify how particle-cell-matrix interactions work in concert to control the biophysics of PCNs at the cell surface during vaporization. To engage and train a new generation of diverse scientists in emerging biotechnologies, such as those explored here, this project will develop and implement an outreach program to integrate underrepresented K-12 students in STEM research. Activities will include incorporating underserved high-school students into undergraduate engineering design teams, and the creation of an Ultrasound Olympics workshop to engage grade 6-12 teachers and integrate bioengineering and acoustics concepts into the classroom. By linking the proposed research program with outreach activities, this project will contribute to the development of a competitive STEM workforce capable of tackling diverse challenges in biomaterials design, molecular biophysics and bioimaging.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.