Amelioration of systemic antitumor immune responses in cocktail therapy by immunomodulatory nanozymes.

Abstract

Nanozymes that mimic natural enzyme–like activities have gradually emerged in cancer therapy. To overcome the bottlenecks of single-mode nanozymes, including “off-target” toxicity and ineffectiveness toward metastatic cancers, we designed magnetic nanoparticle–based multifunctional visualized immunomodulatory nanozymes. Besides the partial initiation of the prime immune response by intrinsic immunogenicity, as a smart drug delivery system with a temperature- and pH-sensitive dual response to the tumor microenvironment, these nanozymes released immune agonists to boost enhanced systemic immune response, eventually ameliorating the cancer immune microenvironment through many aspects: activating dendritic cells, improving the function of CD8+ T cells, and decreasing the population of myeloid-derived suppressor cells, which inhibited both primary and metastatic cancers. Mechanistically, these nanozymes regulated the reactive oxygen species–related Akt signaling pathway and consequently activated cell apoptosis–related signaling pathways, which provided a deeper understanding of the synergistic mechanism of multifunctional nanozymes. Our findings offer a promising imaging-guided cocktail therapy strategy through immunomodulatory nanozymes.