Tunable mechanobiology of ferroptotic cancer cells using nanoencapsulation increases the efferocytosis efficiency

While the importance of regulated cell death (RCD) in therapeutic applications is undeniable, there are still mysteries enshrouding the immune system’s response to the different RCD modalities. Previous research has shown that mechanical properties can affect the phagocytic uptake of dead cells. As the elasticity of dying cells drops significantly, the question arises as to what effect these mechanobiology changes have on phagocytic uptake. Among various encapsulation methods, Layer-by-Layer (LbL) offers extensive flexibility in the surface design and their interfacial nano-architectonics. Here we show that applying LBL coating to ferroptotic cancer cells significantly increases their elasticity. The increase leads to a significant improvement of efferocytosis of the ferroptotic cancer cells by primary murine macrophages. This study demonstrates the essential role of the elasticity of ferroptotic cancer cells, and dead cells in general, in modulating their efferocytosis and may help to develop strategies to regulate efferocytosis, improve tumor antigen targeting to immune cells, and utilize cell nano-coatings as drug delivery systems for cancer therapy.