Self-degradable poly(β-amino ester)s promote endosomal escape of antigen and agonist

Vaccination with subunit nanovaccines is a promising strategy to combat virus infection and tumor development. However, immunogenicity of present nanovaccines is still unsatisfied for clinical translation. Here, we developed a nanovaccine loading a STING agonist, 2'3'-cGAMP and, a model subunit antigen, OVA, by using a well-defined self-degradable poly(β-amino ester)s to treat B16F10-OVA melanoma tumors. The polymer underwent slow hydrolysis at pH 5.5 but self-degraded induced by the amino groups along the polyester chain at pH > 6.5. It is shown that the self-degradation products facilitated the release of 2'3'-cGAMP and OVA from early endolysome to the cytosol, where the two components strongly activated CD8⁺ T lymphocytes (CTLs) and significantly enhanced Ifn1, TNF, Cxcl9, and Cxcl10 expression. In turn, the tumor microenvironment was remolded from cold to hot. Moreover, the nanovaccine could be quickly drained to sentinel lymph nodes after intratumoral injection. The nanovaccine with strong immunogenicity also could reduce the side effects of systemic inflammatory reaction caused by molecular 2'3'-cGAMP. The tumor progression of animals was inhibited, and their survival rates increased significantly. Thus, the multifunctional biodegradable material provided a new delivery system for a cancer vaccine to translate to clinics.