Identification of Cell Receptors Responsible for Recognition and Binding of Lipid Nanoparticles

Effective delivery of lipid nanoparticles (LNPs) and their organ- or cell-type targeting are paramount for therapeutic success. Achieving this requires a comprehensive understanding of protein corona dynamics and the identification of cell receptors involved in the recognition and uptake of LNPs. We introduce a simple, fast, and in situ strategy by a biosensor-based "Fishing" method to uncover protein corona formation on LNPs and identify key receptors of human blood cells that are responsible for the recognition and binding of human plasma corona on the surface of LNPs. Unexpectedly, we observed a significant presence of immunoglobulins with high abundance, especially anti-PEG antibodies, within the LNP corona. These antibodies, along with complement opsonization, drive colony-stimulating factor 2 receptor β (CSF2RB)-mediated phagocytosis by human myeloid cells. These compositions of the human plasma corona and their interactions with neighboring proteins are critical for the recognition and binding of LNPs by cell receptors and cellular uptake. Our findings highlight the pivotal role of anti-PEG antibodies in the circulation and phagocytosis of LNPs in vivo. This approach offers profound insights into nanomaterial behavior in vivo, paving the way for the enhanced design and efficacy of LNP-based therapies.