The PI’s lab’s long-term research goal is to design nanoparticles to transport drugs across and study biological barrier-nanoparticle interfaces to improve therapeutic outcomes, particularly those modulating the immune response. This CAREER proposal will be the first stepping-stone toward achieving the long-term research goal. Therapeutic treatments targeting the immune system range from classic vaccines to allergen immunotherapy to cancer immunotherapies. Targeting lymph nodes directly has been shown to significantly enhance efficacy of immunotherapies, both for vaccination and immunotherapies. This is often done via direct injection into the lymph nodes, but using the natural transport function of lymphatic vessels, by employing small nanoparticles, is a promising, less invasive alternative. In this proposal, the PI will address the gaps in knowledge on how material properties like shape and surface chemistry as well as fluid flow within tissues affect nanoparticle transport by lymphatic vessels. The results from the proposed studies will provide a set of design criteria for developing vaccines and immunotherapies that non-invasively target lymph nodes, which will also enhance acceptability and translatability of such therapeutics. Furthermore, lymphatic transport targeting nanoparticle therapeutics could significantly enhance efficacy of immunotherapies and vaccines, by e.g. providing longer protection against pathogens or enhancing response to cancer immunotherapy, all while reducing side effects and required doses. The proposed research will be integrated into a transformative education and outreach program to teach critical thinking and interpretation of data and promote inclusion and retention of underrepresented groups, particularly women, in engineering. Toward the first goal, the PI will design in-class laboratory exercises that are supplemented with real-world data from the research objectives to illustrate complexities of biological systems. Diversity in engineering is still far below that of the general population and research has shown that diversity in teams and researchers increases creativity, achievement, and outside-the-box thinking. The PI has developed a 3-pronged approach that builds upon two main principles identified to aid in retention and recruitment of diverse groups in STEM: mentorship and inclusive leadership. For this CAREER award, the PI will build generational and peer mentorship programs, increase dissemination of mentorship training programs, design diversity education modules to educate the next and current generation of scientists on promoting inclusive environments, and finally, build early-stage interventions by partnering with rural elementary schools to recruit women and underrepresented groups into STEM careers. The long-term outcome is to strengthen the participation of diverse groups in STEM through exposure and educational opportunities and tools to maintain and encourage diversity in teams and research at all levels.
The PI’s lab’s long-term research goal is to design nanoparticles to study biological barrier-nanoparticle interfaces to improve therapeutic outcomes. This CAREER award will be the first stepping-stone to achieve the long-term research goal by investigating the nanoparticle interface with lymphatic vessels (‘lymphatics’). Lymphatics have crucial transport roles, shuttling antigens and particulates from peripheral tissues to the draining lymph nodes (dLNs), where the adaptive immune response is shaped. Reaching the dLNs has been shown to particularly amplify the effectiveness of immunotherapies and vaccines and can be achieved by targeting lymphatics using small particulates between 10 – 200 nm. But many questions remain unanswered: how do material properties, like shape and surface characteristics, affect transendothelial transport of nanoparticles and the mechanisms involved in this transport? In this CAREER award, the PI will 1) investigate the effects of nanoparticle properties such as shape and surface chemistry on their transport by lymphatics, 2) determine how interstitial flow modulates transport of these different nanoparticle formulations, 3) assess nanoparticle protein corona formation and stability in lymph fluid, and 4) elucidate the cellular mechanisms used by lymphatics to transport nanoparticles with different material properties. The PI’s long-term educational goal is to develop experiential learning experiences and build educational tools to recruit and retain underrepresented groups in engineering. The first educational goal will be to design in-class laboratory exercises that are supplemented with real-world data from the research objectives to illustrate complexities of biological systems. Research has shown that diversity in teams and researchers increases creativity, achievement, and outside-the-box thinking. The PI has developed a 3-pronged approach that builds upon two main principles identified to aid in retention and recruitment of diverse groups in STEM: mentorship and inclusive leadership. The PI will 1) build generational and peer mentorship programs, 2) increase dissemination of mentorship training programs, 3) design diversity education modules to educate the next and current generation of scientists on promoting inclusive environments, and 4) build early-stage interventions by partnering with rural elementary schools to recruit women and underrepresented groups into STEM careers. The proposed research will lead to crucial advances in fundamental understanding of how nanoparticle properties 1) modulate transport by lymphatics, particularly in the context of interstitial fluid flow, and 2) affect cellular mechanisms used by lymphatics to transport nanoparticles across the vessel wall. This fundamental understanding will provide rational material-based design criteria for nanoparticle platforms that can be used as probes to study lymphatic transport physiology and to deliver immunotherapies and vaccines.
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.
