Surface engineering of NIR-II luminescent gold nanoclusters for brain glioma-targeted imaging

Ultrasmall gold nanoclusters (AuNCs) with photoluminescence in the second near-infrared region (NIR-II) have emerged as promising probes for <i>in vivo</i> biomedical applications. However, it remains a challenge to utilize NIR-II-emitting AuNCs for imaging brain glioblastoma (GBM), which is highly lethal and hard to diagnose in time. Herein, we have presented systematic investigations on the brain delivery and GBM targeting efficacies of NIR-II-emitting AuNCs protected by different ligands. We first synthesized four types of AuNCs with surface coatings of small thiolated ligands and proteins, and then studied their <i>in vitro</i> penetration capability into the blood-brain barrier (BBB) and <i>in vivo</i> GBM targeting performances. It was found that the BBB permeability of AuNCs determined by the <i>in vitro</i> transwell model was not evidently affected by the surface ligands. Significantly, AuNCs protected by albumin exhibited notably extended blood circulation and less skull binding compared to those protected by small ligands, enabling superior <i>in vivo</i> brain GBM-targeted NIR-II PL imaging. We also modified the albumin-AuNCs with targeting peptides to improve <i>in vivo</i> imaging contrast. Additionally, AuNCs had negligible toxic effects on major organs as well as brain tissues and neurons, corroborating their good biocompatibility. This study examined the surface engineering of NIR-II luminescent AuNCs for brain GBM targeting, which may offer insights into the future design of AuNCs for bioapplications.