Agradecimentos: This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001, grant #2020/01218–3, São Paulo Research Foundation (FAPESP), National Council for Scientific and Technological Development (CNPq), and Fund for Support to Teaching, Research and Outreach Activities – FAEPEX – UNICAMP Ver menos

Abstract: Solid lipid nanoparticles (SLN) are used in various fields such as pharmaceutical, cosmetic, and biomedical research and show promising results in delivering biomolecules. SLN formulations are made with solid lipids (at room and body temperature) stabilized with surfactants and co-surfactants that may guarantee specific properties. Typically, these compounds have high stability, allow large-scale production, and are biodegradable. Since most of these SLNs are formulated with biodegradable materials, they are assumed to have low toxicity or are nontoxic. Therefore, this assumption introduced experimental bias, making SLN toxicity an often overlooked area; moreover, few studies have focused on this topic. Here, we critically review the literature, focusing on blank controls (i.e., SLN formulations without cargo) and their ability to trigger signaling pathways, cellular outcomes, and cytotoxicity. We found that SLN can trigger or disturb many cell signaling pathways; thus, we emphasize the importance of testing the biocompatibility and cytotoxicity of empty SLN. Overall, more attention should be paid to the possible cytotoxic effects of SLN, which is still an open topic, showing that this topic needs further investigation. Therefore, a detailed understanding of SLN toxicity, particularly for biomedical applications, can significantly impact the transfer of SLN formulations from the laboratory bench to the bedside Ver menos