Sono‐Immunotherapeutic Nanocapturer to Combat Multidrug‐Resistant Bacterial Infections

Cancer cells resist to the host immune antitumor response via multiple suppressive mechanisms, including the overexpression of PD-L1 that exhausts antigen-specific CD8+ T cells through PD-1 receptors. Checkpoint blockade antibodies against PD-1 or PD-L1 have shown unprecedented clinical responses. However, limited host response rate underlines the need to develop alternative engineering approaches. Here, engineered cellular nanovesicles (NVs) presenting PD-1 receptors on their membranes, which enhance antitumor responses by disrupting the PD-1/PD-L1 immune inhibitory axis, are reported. PD-1 NVs exhibit a long circulation and can bind to the PD-L1 on melanoma cancer cells. Furthermore, 1-methyl-tryptophan, an inhibitor of indoleamine 2,3-dioxygenase can be loaded into the PD-1 NVs to synergistically disrupt another immune tolerance pathway in the tumor microenvironment. Additionally, PD-1 NVs remarkably increase the density of CD8+ tumor infiltrating lymphocytes in the tumor margin, which directly drive tumor regression.

Bacterial mechanisms of drug resistance operate at sequential lines of defense tackling drug at entry, accumulation, target binding, or downstream toxicity. These mechanisms are encoded by genomic changes ranging in scale from point mutations, through assembly of preexisting genetic elements, to horizontal import of genes from the environment. A many-to-many relationship prevails between resistance mechanisms and the spectrum of genetic changes encoding them.