{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/10415"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/10415","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Cooperativity: Physiologic Cornerstone and Emerging Therapeutic Design Principle","abstract":"The content of this work is based on the previously published articles that are cited below.","abstract_html":"The content of this work is based on the previously published articles that are cited below.","abstract_has_math":false,"creators":["Wilhelm, Jonathan Louis"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Sumer, Baran","Gao, Jinming","Li, Bo","Lea, Jayanthi","Farrar, J. David"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-09-20T22:11:05Z","date_published":"2024-09-20T22:11:05Z","updated_at":"2026-07-24T05:52:38Z","subjects":["Cancer Vaccines","Nanoparticles","Neoplasms","Polymers","T-Lymphocytes"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["Wilhelm, J., Wang, Z., Sumer, B. D., & Gao, J. (2020). Exploiting nanoscale cooperativity for precision medicine. Adv Drug Deliv Rev, 158, 63-72. https://doi.org/10.1016/j.addr.2020.08.012","Wilhelm, J., Quinones-Perez, M., Wang, J., Wang, X., Basava, V. S., & Gao, J. (2021). Antigen folding improves loading efficiency and antitumor efficacy of PC7A nanoparticle vaccine. J Control Release, 329, 353-360. https://doi.org/10.1016/j.jconrel.2020.11.056","Feng, Q., Wilhelm, J., & Gao, J. (2019). Transistor-like Ultra-pH-Sensitive Polymeric Nanoparticles. Acc Chem Res, 52(6), 1485-1495. https://doi.org/10.1021/acs.accounts.9b00080","Huang, T., Feng, Q., Wang, Z., Li, W., Sun, Z., Wilhelm, J., Huang, G., Vo, T., Sumer, B. D., & Gao, J. (2021). Tumor-Targeted Inhibition of Monocarboxylate Transporter 1 Improves T-Cell Immunotherapy of Solid Tumors. Adv Healthc Mater, 10(4), e2000549. https://doi.org/10.1002/adhm.202000549","Wang, X., Wilhelm, J., Li, W., Li, S., Wang, Z., Huang, G., Wang, J., Tang, H., Khorsandi, S., Sun, Z., Evers, B., & Gao, J. (2020). Polycarbonate-based ultra-pH sensitive nanoparticles improve therapeutic window. Nat Commun, 11(1), 5828. https://doi.org/10.1038/s41467-020-19651-7","Li, S., Luo, M., Wang, Z., Feng, Q., Wilhelm, J., Wang, X., Li, W., Wang, J., Cholka, A., Fu, Y. X., Sumer, B. D., Yu, H., & Gao, J. (2021). Prolonged activation of innate immune pathways by a polyvalent STING agonist. Nat Biomed Eng, 5(5), 455-466. https://doi.org/10.1038/s41551-020-00675-9","Jiang, X., Wang, J., Zheng, X., Liu, Z., Zhang, X., Li, Y., Wilhelm, J., Cao, J., Huang, G., Zhang, J., Sumer, B., Lea, J., Lu, Z., Gao, J., & Luo, M. (2022). Intratumoral administration of STING-activating nanovaccine enhances T cell immunotherapy. J Immunother Cancer, 10(5). https://doi.org/10.1136/jitc-2021-003960","1456721249"],"render_values":[{"text":"Wilhelm, J., Wang, Z., Sumer, B. D., & Gao, J. (2020). Exploiting nanoscale cooperativity for precision medicine. Adv Drug Deliv Rev, 158, 63-72. https://doi.org/10.1016/j.addr.2020.08.012","href":"https://doi.org/10.1016/j.addr.2020.08.012","code":true},{"text":"Wilhelm, J., Quinones-Perez, M., Wang, J., Wang, X., Basava, V. S., & Gao, J. (2021). Antigen folding improves loading efficiency and antitumor efficacy of PC7A nanoparticle vaccine. 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D., & Gao, J. (2020). Exploiting nanoscale cooperativity for precision medicine. Adv Drug Deliv Rev, 158, 63-72. https://doi.org/10.1016/j.addr.2020.08.012","Wilhelm, J., Quinones-Perez, M., Wang, J., Wang, X., Basava, V. S., & Gao, J. (2021). Antigen folding improves loading efficiency and antitumor efficacy of PC7A nanoparticle vaccine. J Control Release, 329, 353-360. https://doi.org/10.1016/j.jconrel.2020.11.056","Feng, Q., Wilhelm, J., & Gao, J. (2019). Transistor-like Ultra-pH-Sensitive Polymeric Nanoparticles. Acc Chem Res, 52(6), 1485-1495. https://doi.org/10.1021/acs.accounts.9b00080","Huang, T., Feng, Q., Wang, Z., Li, W., Sun, Z., Wilhelm, J., Huang, G., Vo, T., Sumer, B. D., & Gao, J. (2021). Tumor-Targeted Inhibition of Monocarboxylate Transporter 1 Improves T-Cell Immunotherapy of Solid Tumors. Adv Healthc Mater, 10(4), e2000549. https://doi.org/10.1002/adhm.202000549","Wang, X., Wilhelm, J., Li, W., Li, S., Wang, Z., Huang, G., Wang, J., Tang, H., Khorsandi, S., Sun, Z., Evers, B., & Gao, J. (2020). Polycarbonate-based ultra-pH sensitive nanoparticles improve therapeutic window. Nat Commun, 11(1), 5828. https://doi.org/10.1038/s41467-020-19651-7","Li, S., Luo, M., Wang, Z., Feng, Q., Wilhelm, J., Wang, X., Li, W., Wang, J., Cholka, A., Fu, Y. X., Sumer, B. D., Yu, H., & Gao, J. (2021). Prolonged activation of innate immune pathways by a polyvalent STING agonist. Nat Biomed Eng, 5(5), 455-466. https://doi.org/10.1038/s41551-020-00675-9","Jiang, X., Wang, J., Zheng, X., Liu, Z., Zhang, X., Li, Y., Wilhelm, J., Cao, J., Huang, G., Zhang, J., Sumer, B., Lea, J., Lu, Z., Gao, J., & Luo, M. (2022). Intratumoral administration of STING-activating nanovaccine enhances T cell immunotherapy. 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Inspired by nature, this dissertation explores a design principle that incorporates nanoscale cooperativity and phase transition to sense and amplify physiological signals to improve the therapeutic outcome. Using ultra-pH-sensitive (UPS) nanoparticles as an example, I will first demonstrate how all-or-nothing protonation cooperativity during micelle assembly/disassembly can be exploited to increase dose accumulation and achieve rapid drug release in acidic microenvironments. In ongoing development, I will then present three facets of investigation into a UPS-based nanovaccine platform using the polymer PC7A for cancer immunotherapy. The first line of inquiry involves a systematic investigation of physicochemical properties of the nanovaccine with a detailed characterization of the biophysical relationship between PC7A nanoparticles and peptide-based antigens. This work identifies dual-cooperative phase transition of the micelle and peptide, both of which are necessary for downstream vaccine efficacy. The second line of inquiry comprises the development of a biodegradable series of UPS nanoparticles. This work culminates with the investigation of a biodegradable nanovaccine and its improved safety profiles compared with the nondegradable predecessor. Finally, the third line of inquiry explores the roles of myeloid cells in governing the T cell responses following vaccination by PC7A and subsequent therapeutic resistance. This work identifies a population of macrophages which interacts with and suppresses T cell activity, leading to therapeutic resistance, and culminates with the development of combinatorial therapies to overcome resistance. Together, these bodies of work cooperate to enable optimized nanoparticle vaccination strategies through the improvement of biophysical stability, physiologic safety profiles, and long-term efficacy in late-stage tumors."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Cooperativity: Physiologic Cornerstone and Emerging Therapeutic Design Principle"]}]}],"canonical_facts":{"dc:contributor":["Sumer, Baran","Gao, Jinming","Li, Bo","Lea, Jayanthi","Farrar, J. David"],"dc:creator":["Wilhelm, Jonathan Louis"],"dc:date":["2024-09-20T22:11:05Z","2022-08","August 2022"],"dc:description":["The content of this work is based on the previously published articles that are cited below.","Precise spatiotemporal control of molecular transport is vital to functional physiological systems. Nature evolved to apply macromolecular cooperativity to achieve precision over systemic delivery of important molecules. In drug delivery, conventional nanocarriers employ inert materials and rely on passive accumulation for tissue targeting and diffusion for drug release. Early clinical studies show these nanodrugs have not delivered the anticipated impact on therapy. Inspired by nature, this dissertation explores a design principle that incorporates nanoscale cooperativity and phase transition to sense and amplify physiological signals to improve the therapeutic outcome. Using ultra-pH-sensitive (UPS) nanoparticles as an example, I will first demonstrate how all-or-nothing protonation cooperativity during micelle assembly/disassembly can be exploited to increase dose accumulation and achieve rapid drug release in acidic microenvironments. In ongoing development, I will then present three facets of investigation into a UPS-based nanovaccine platform using the polymer PC7A for cancer immunotherapy. The first line of inquiry involves a systematic investigation of physicochemical properties of the nanovaccine with a detailed characterization of the biophysical relationship between PC7A nanoparticles and peptide-based antigens. This work identifies dual-cooperative phase transition of the micelle and peptide, both of which are necessary for downstream vaccine efficacy. The second line of inquiry comprises the development of a biodegradable series of UPS nanoparticles. This work culminates with the investigation of a biodegradable nanovaccine and its improved safety profiles compared with the nondegradable predecessor. Finally, the third line of inquiry explores the roles of myeloid cells in governing the T cell responses following vaccination by PC7A and subsequent therapeutic resistance. This work identifies a population of macrophages which interacts with and suppresses T cell activity, leading to therapeutic resistance, and culminates with the development of combinatorial therapies to overcome resistance. Together, these bodies of work cooperate to enable optimized nanoparticle vaccination strategies through the improvement of biophysical stability, physiologic safety profiles, and long-term efficacy in late-stage tumors."],"dc:format":["application/pdf"],"dc:identifier":["Wilhelm, J., Wang, Z., Sumer, B. D., & Gao, J. (2020). Exploiting nanoscale cooperativity for precision medicine. Adv Drug Deliv Rev, 158, 63-72. https://doi.org/10.1016/j.addr.2020.08.012","Wilhelm, J., Quinones-Perez, M., Wang, J., Wang, X., Basava, V. S., & Gao, J. (2021). Antigen folding improves loading efficiency and antitumor efficacy of PC7A nanoparticle vaccine. J Control Release, 329, 353-360. https://doi.org/10.1016/j.jconrel.2020.11.056","Feng, Q., Wilhelm, J., & Gao, J. (2019). Transistor-like Ultra-pH-Sensitive Polymeric Nanoparticles. Acc Chem Res, 52(6), 1485-1495. https://doi.org/10.1021/acs.accounts.9b00080","Huang, T., Feng, Q., Wang, Z., Li, W., Sun, Z., Wilhelm, J., Huang, G., Vo, T., Sumer, B. D., & Gao, J. (2021). Tumor-Targeted Inhibition of Monocarboxylate Transporter 1 Improves T-Cell Immunotherapy of Solid Tumors. Adv Healthc Mater, 10(4), e2000549. https://doi.org/10.1002/adhm.202000549","Wang, X., Wilhelm, J., Li, W., Li, S., Wang, Z., Huang, G., Wang, J., Tang, H., Khorsandi, S., Sun, Z., Evers, B., & Gao, J. (2020). Polycarbonate-based ultra-pH sensitive nanoparticles improve therapeutic window. Nat Commun, 11(1), 5828. https://doi.org/10.1038/s41467-020-19651-7","Li, S., Luo, M., Wang, Z., Feng, Q., Wilhelm, J., Wang, X., Li, W., Wang, J., Cholka, A., Fu, Y. X., Sumer, B. D., Yu, H., & Gao, J. (2021). Prolonged activation of innate immune pathways by a polyvalent STING agonist. Nat Biomed Eng, 5(5), 455-466. https://doi.org/10.1038/s41551-020-00675-9","Jiang, X., Wang, J., Zheng, X., Liu, Z., Zhang, X., Li, Y., Wilhelm, J., Cao, J., Huang, G., Zhang, J., Sumer, B., Lea, J., Lu, Z., Gao, J., & Luo, M. (2022). Intratumoral administration of STING-activating nanovaccine enhances T cell immunotherapy. J Immunother Cancer, 10(5). https://doi.org/10.1136/jitc-2021-003960","https://hdl.handle.net/2152.5/10415","1456721249"],"dc:language":["en"],"dc:relation":["https://doi.org/10.1016/j.addr.2020.08.012","https://doi.org/10.1016/j.jconrel.2020.11.056","https://doi.org/10.1021/acs.accounts.9b00080","https://doi.org/10.1002/adhm.202000549","https://doi.org/10.1038/s41467-020-19651-7","https://doi.org/10.1038/s41551-020-00675-9","https://doi.org/10.1136/jitc-2021-003960"],"dc:subject":["Cancer Vaccines","Nanoparticles","Neoplasms","Polymers","T-Lymphocytes"],"dc:title":["Cooperativity: Physiologic Cornerstone and Emerging Therapeutic Design Principle"],"dc:type":["Thesis","text"]},"updated_at":"2026-07-24T05:52:38Z"}