Neutrophil-mediated transport is crucial for delivery of short-circulating magnetic nanoparticles to tumors.

Recently neutrophil-based nanoparticles (NPs) drug delivery systems have gained considerable attention in cancer therapy. Numerous studies have been conducted to identify optimal NPs parameters for passive tumor targeting, while there is a fundamental dearth of knowledge about the factors governing cell-mediated delivery. Here, by using intravital microscopy and magnetic resonance imaging, we describe accumulation dynamics of 140 nm magnetic cubes and clusters in murine breast cancer (4T1) and colon cancer (CT26) models. Notwithstanding rapid clearance from the blood flow, NPs readily accumulated in tumors at later time points. Both NPs types were captured mostly by intravascular neutrophils immediately after injection, and transmigration of NPs-bound neutrophils through the vessel wall was first shown in real-time. A dramatic drop in NPs accumulation upon Ly6G and Gr1 depletion further confirmed the role of neutrophils as a biocarrier for targeting tumors. Of note, for shorter circulating NPs, a cell-dependent delivery route was more impactful, while the accumulation of longer circulating counterpart was less compromised by neutrophil depletion. Neutrophil-mediated transport was also shown to depend on tumor type, with more efficiency noted in neutrophil-rich tumors. Revealing NPs characteristics and host factors influencing the neutrophil-based tumor targeting will help to rationally design drug delivery systems for improved cancer treatment. STATEMENT OF SIGNIFICANCE: Utilizing host cells as trojan horses for delivery nanodrugs to tumor site is a promising approach for cancer therapy. However, it is not clear yet how nanoparticles characteristics and tumor properties affect the efficiency of cell-based nanoparticles transport. Here, we compare neutrophil-based delivery of different-shaped magnetic nanoparticles (cubes and clusters) in two tumor models. The results suggest that neutrophil-mediated route is more impactful for rapidly cleared cubes, than for longer circulating clusters. The efficiency of cell-based accumulation also correlated with the level of neutrophils recruitment to different tumor types. These finding are important for rationale design of nanocarriers and predicting the efficiency of neutrophil-mediated drug delivery between patients and tumor types.