Effects of Etching and Delamination on Biocompatibility of Ti-Based MXenes

MXenes, a class of two-dimensional transition metal carbides and nitrides, have emerged as promising candidates for biomedical applications due to their electrical conductivity, photothermal response, and rich surface chemistry. However, their biocompatibility is highly sensitive to synthesis conditions, particularly etching and delamination strategies. In this study, we systematically investigated the influence of different synthesis routes─using acidic (concentrated or diluted HF/HCl) etching and Li+ versus Na+ intercalation─on the surface chemistry, structural integrity, and biological behavior of Ti3C2Tx and its carbonitride analog Ti3C1.5N0.5Tx. Detailed physicochemical characterization revealed that water-assisted etching and Na+ intercalation enhanced hydroxylation and reduced fluorine terminations. Biological assays using human keratinocytes (HaCaT) demonstrated that Ti3C1.5N0.5Tx exhibited superior biocompatibility compared to Ti3C2Tx, with lower cytotoxicity, diminished ROS generation, minimal inflammatory signaling (IL-6 and IL-8 interleukins), and preserved wound healing capacity. Among Ti3C2Tx variants, the combination of diluted etchant and Na+ intercalation significantly improved biological tolerance, minimizing apoptosis and oxidative stress. These findings underscore the critical role of surface chemistry in MXene-cell interactions and offer a practical guide to engineering safer MXenes for biomedical use.