Manganese-Driven Plasmid Nanofibers Formed In Situ for Cancer Gene Delivery and Metalloimmunotherapy

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 MnO2-OVA-CDA-mem, formed by the coencapsulation of manganese dioxide (MnO2), 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, Mn2+ released from MnO2 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 Mn2+ 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, MnO2-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.