Engineered Macrophages: A Safe-by-Design Approach for the Tumor Targeting Delivery of Sub-5 nm Gold Nanoparticles.

Ultrasmall nanoparticles (NPs) are a promising platform for the diagnosis and therapy of cancer, but the particles in sizes as small as several nanometers have an ability to translocate across biological barriers, which may bring unpredictable health risks. Therefore, it is essential to develop workable cell-based tools that can deliver ultrasmall NPs to the tumor in a safer manner. Here, this work uses macrophages as a shuttle to deliver sub-5 nm PEGylated gold (Au) NPs to tumors actively or passively, while reducing the accumulation of Au NPs in the brain. This work demonstrates that sub-5 nm Au NPs can be rapidly exocytosed from live macrophages, reaching 45.6% within 24 h, resulting in a labile Au NP-macrophage system that may release free Au NPs into the blood circulation in vivo. To overcome this shortcoming, two straightforward methods are used to engineer macrophages to obtain "half-dead" and "dead" macrophages. Although the efficiency of engineered macrophages for delivering sub-5 nm Au NPs to tumors is 2.2-3.8% lower than that of free Au NPs via the passive enhanced permeability and retention effect, this safe-by-design approach can dramatically reduce the accumulation of Au NPs in the brain by more than one order of magnitude. These promising approaches offer an opportunity to expand the immune cell- or stem cell-mediated delivery of ultrasmall NPs for the diagnosis and therapy of diseases in a safer way in the future.