The combination of chemotherapeutic agents with immune stimulating agents for treating degenerative diseases, called chemoimmunotherapy, has emerged as a promising
cancer treatment modality. Despite the tremendous potential, chemoimmunotherapy by the combination of drugs and immune stimulators often suffers because of the lack of controlled delivery nanostructures in the microenvironment. To this end, we show that by using pH-responsive smart nanocubes (NCs),
cancer cells and
tumor-associated immune cells can be precisely targeted with a chemotherapeutic agent (
doxorubicin, DOX) and immune stimulating agent (plasmid
ovalbumin, pOVA) for enhanced chemoimmunotherapy. The pH-responsive smart NCs protect payloads from nuclease degradation and avoid renal clearance and undergo supersensitive structural change at the extracellular
tumor regions that mediate efficient release. Concurrent release of pOVA
vaccines encoding
tumor-specific
antigen laden with polyplexes were loaded on
tumor-associated immune cells and produce
antigen-specific humoral immune response, whereas DOX enables effective infiltration into the
cancer cells and is involved in the eradication of
tumor tissues. The amount of anti-OVA
IgG1 antibody produced by the
intravenous administration of NC formulation was similar to that of free OVA formulation. Importantly, the combined delivery of pDNA and DOX using NCs showed significantly enhanced antitumor efficacy in B16/OVA
melanoma tumor xenografts, which remarkably outperforms the monotherapy counterparts. These results suggest that pH-responsive smart NCs laden with pDNA and DOX provide a promising nanostructure for chemoimmunotherapy that simultaneously involves
cancer cell killing and stimulates
antigen-specific immune response to prevent
cancer recurrence.