Manganese-Driven Plasmid Nanofibers Formed <i>In Situ</i> for Cancer Gene Delivery and Metalloimmunotherapy
Jiexin Li, Ruiqi Yang, Chen Zhang, Jonathan F. Lovell, Yumiao Zhang
Abstract
While nucleic-acid-based cancer vaccines hold therapeutic potential, their limited immunogenicity remains a challenge due in part to the low efficiency of cytoplasmic delivery caused by lysosomal entrapment. In this work, we found that plasmids encoding both an antigen and a STING agonist protein adjuvant can self-assemble into coordination nanofibers, triggered by manganese ions. We developed a strategy to construct a DNA vaccine, termed MnO 2 -OVA-CDA-mem, formed by the coencapsulation of manganese dioxide (MnO 2 ), an antigen-expressing plasmid (encoding ovalbumin, OVA), and an adjuvant enzyme-expressing plasmid (encoding STING agonist, CDA) within dendritic cell (DC) membranes. Upon uptake into acidic lysosomes, Mn 2+ released from MnO 2 triggered the nucleic acids to undergo a morphological change from nanospheres (∼180 nm diameter) to nanofibers (∼1 μm length), resulting in an increase in mechanical strength by about 9-fold and consequently lysosomal membrane disruption. The antigen OVA and adjuvants Mn 2+ and CDA in the cytoplasm triggered strong DC activation and antigen-specific CD8 + T cell metalloimmune responses, significantly inhibiting the growth of B16-OVA tumors and inducing long-term immune memory. Altogether, MnO 2 -OVA-CDA-mem holds potential as a platform for nucleic acid antigen and adjuvant delivery using an in situ self-assembly strategy in a metal-driven, stimulus-responsive, and programmable manner for cancer metalloimmunotherapy.