UCLA

Protein therapeutics show promising potential for treating a wide range of diseases associated with immune dysfunction, yet their broader application is limited by disadvantages such as poor stability, short half-life, and potential immunogenicity. To address these challenges, this dissertation presents the development of protein nanocapsules that encapsulate protein molecules within a thin layer of polymer, conferring protein therapeutics with enhanced stability, prolonged circulation half-life, and reduced immunogenicity. Specifically, this dissertation discusses the application of protein nanocapsules to modulate immune responses in two critical healthcare challenges: viral infection and cancer. The first part of this dissertation explores catalase nanocapsules to alleviated symptoms related to SARS-CoV-2 infection. These nanocapsules act by mitigating hyperinflammation and suppressing viral replication through reducing the levels of hydrogen peroxide-a key immunostimulatory molecule that escalates during viral infection. The efficacy of catalase nanocapsules has been validated in SARS-CoV-2 infection model using non-human primates, showcasing its potential as a novel therapeutic strategy. The second part of this dissertation focuses on the design of lactate oxidase nanocapsules, which counteract tumor immunosuppression and enhance the efficacy of cancer immunotherapy. By targeting excessive lactate, a byproduct of tumor metabolism, lactate oxidase nanocapsules not only alleviate tumor immunosuppression but also produce hydrogen peroxide, which further recruits and activates immune cells in the tumor microenvironment. This dual-action mechanism improves anti-tumor immunity and boosts the efficacy of immune checkpoint blockade therapy in multiple solid tumor models. The innovative development of nanocapsules of different protein therapeutics allows us to regulate immune responses, such as mitigating hyperinflammation or activating antitumor immunity, offering a promising strategy to manage diseases related to immune dysfunction.