CAREER: Engineering Polymeric Nanomaterials for Programming Innate Immunity

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1554623Wilson, John T. From cancer, to diabetes, to chronic infections, the immune system plays an important role in nearly every disease. Accordingly, harnessing the power and specificity of the immune system has enormous - and still largely untapped - potential to improve human health and wellbeing. However, there remains an unmet need for technologies that enable precise and predictable "programming" of the correct type of immune response necessary to yield a desired outcome. The goal of this CAREER Award is to develop new synthetic materials for "encoding" immunological messages and tightly regulating their delivery to the organs, cells, and pathways of the immune system. In this project, the PI will engineer pathogen-mimicking polymer nanoparticles for connecting multiple immunological cues and controlling their delivery to the appropriate pathways of immune cells. This research will address a fundamental need for new tools to control, understand, and harness the immune system, which has significant ramifications in vaccine development, cancer immunotherapy, and treatment of autoimmune disorders. Additionally, the PI will develop an educational outreach program that creates hands-on, inquiry-based lessons to catalyze active engagement in STEM areas by underprivileged students, while increasing awareness about vaccines, the immune system, and the importance of interdisciplinary science. Cells of the innate immune system sense invading pathogens or pathologic tissue using pattern recognition receptors (PRRs) that are localized on the cell surface, in endosomal compartments, and in the cytosol. There is significant crosstalk between these pathways, and the integration of signals emanating from these receptors triggers and shapes the phenotype and magnitude of an immune response. Therefore, regulating the delivery of immunologic cues to multiple receptors localized throughout a cell is fundamental to controlling immunity. Yet, there is a lack of synthetic tools that can properly encode these physicochemically diverse cues to confer a desired immunological outcome.The objective of this CAREER Award is to engineer a versatile nanoparticle-based platform for tightly regulating the delivery of molecularly defined activators of innate immune sensing pathways. The overall hypothesis is that polymer vesicles (i.e., polymersomes) engineered with precisely tunable pH-responsive and endosome-destabilizing activity will enable the coordinated delivery of multiple defined cues that trigger surface, endosomal, and cytosolic PRRs. The hypothesis will be tested and the objectives accomplished through the following specific aims: 1) engineer polymersomes with precisely tunable pH-responsive disassembly, release, and endosome destabilizing properties; 2) investigate the effect of polymersome properties on the activity of PRR agonists delivered alone or in combination; 3) demonstrate that polymersomes loaded with multiple PRR agonists can be used to program the magnitude and phenotype of an immune response. The proposed research will lead to the following impactful scientific and technological outcomes: 1) the development of materials that will expand the repertoire of druggable targets for immunomodulation; 2) fundamental knowledge of how materials can be designed to coordinate signaling events originating from diverse receptors localized throughout the cell; and 3) elucidation of new material-dependent synergies between PRRs that can be exploited to enhance and shape immune responses to vaccines. By integrating the synthesis of novel and rationally designed materials with fundamental studies elucidating new structure-activity relationships, the proposed research will have intellectual merit within the biomaterials, biopharmaceutical, and immunology communities.To enhance the broader impacts of this CAREER Award, an integrated research, education, and outreach program will be developed to 1) train high school, undergraduate, and graduate students in bioengineering research; 2) create and broadly disseminate hands-on, inquiry-based educational science lessons for middle and high school classrooms; 3) catalyze active and authentic engagement in STEM subjects by underrepresented and/or underprivileged middle and high school students; 4) increase awareness about vaccines, the immune system, and the importance of interdisciplinary teams in solving grand challenges in health care. In collaboration with the School for Science and Math at Vanderbilt (SSMV) and the Vanderbilt Student Volunteers for Science (VSVS), a 'students teaching students' initiative will be launched to develop an inexpensive, hands-on, mobile lesson kit for middle and high school students in Nashville public schools and rural Tennessee communities.