Involvement of Surface Receptors in the Uptake and Cellular Responses Induced by Cationic Polyamine-Based Carbon Dots...

Cationic polyamine-based carbon dots (CDs) are increasingly being explored for biomedical applications. These ultrasmall (<10 nm) fluorescent nanoparticles, synthesized from organic precursors and functionalized with polyamines, possess a strong positive surface charge that enables efficient complexation and delivery of nucleic acids, making them promising candidates for gene therapy. However, the mechanisms by which the immune system, particularly macrophages, recognizes and responds to these nanomaterials remain poorly understood. In this study, we investigated the role of surface receptors in the uptake and biological effects of cationic polyamine-based CDs in macrophages. Our data showed that Fc receptors and the Toll-like receptor 4 (TLR4) were minimally involved in CD internalization and associated cellular responses in contrast to scavenger receptors (SRs). Indeed, SR inhibition reduced CD-induced cell viability loss, LDH release, and secretion of the pro-inflammatory cytokine IL-1β. Among SRs, SR-A1 was identified as a key receptor mediating CD recognition and toxicity, likely through activation of the MERTK signaling pathway. Importantly, these mechanisms occurred in the absence of serum, indicating that protein corona formation is not required for CD interaction with macrophage surface receptors. Overall, our findings highlight the prominent role of SRs, particularly SR-A1, as receptors recognizing cationic polyamine-based CDs on the surface of macrophages, and provide new insights into the cellular mechanisms underlying the immunotoxicity of these carbon-based nanomaterials.