Abstract Gold nanoclusters (AuNCs) are atomically precise, ultrasmall (2 nm) nanoparticles that exhibit favorable biocompatibility and renal clearance properties1-2. N-heterocyclic carbene (NHC) functionalized gold nanoclusters (NHC-AuNCs) are a new class of nanomaterials with high chemical stability, structural tunability, and strong potential to amplify radiation-induced cytotoxicity 3-4. We have synthesized bis-N-heterocyclic carbene (NHC)-protected Au13 nanoclusters that display intrinsic photoluminescence quantum yields, making them attractive candidates for cancer theranostics. Our objective is to improve their therapeutic performance by enhancing their distribution, increasing their tumor-targeting capability, and employing them as sensitizers for photodynamic therapy and/or radiotherapy (RT). In this work, we developed novel NHC-AuNCs with ∼20-30% reactive oxygen species (ROS) production efficiency, a key property for inducing ROS-mediated DNA damage in cancer cells. We performed in vitro studies, including cytotoxicity, cellular uptake, and PDT potency evaluation, to assess their effectiveness as PDT agents. ICP-MS analyses verified efficient cellular uptake across multiple pancreatic cancer cell lines. Upon PDT irradiation at 10 and 20 J/cm2, treatment with 5 µM NHC-AuNCs induced over 90% cell death, whereas negligible cytotoxicity was observed in both non-AuNC-treated and no-light-treated control groups. These NHC-AuNCs show high PDT efficacy at half the concentration compared to previously tested AuNCs, making them a potent PDT agent. Ongoing work focuses on refining the nanocluster framework to enhance tumor specificity. The incorporation of surface azide groups enables click-chemistry conjugation of targeting peptides to improve tumour targeting. In parallel, in vivo studies assessing biodistribution, PDT efficacy, and survival outcomes in tumor-bearing models are underway to establish the therapeutic potential of these NHC-stabilized AuNCs.The ability of these nanoclusters to act as potent PDT agents provides a powerful nanoplatform for advancing cancer targeted therapy. The ability of various NHC-AuNCs with different photophysical and chemical properties to act as PDT agents will be discussed. References 1 Huang, Y etc., Nat. Nanotechnol. 2023, 18 (6), 637-646. 2 Zhang, X.-D. etc., Enhanced Tumor Accumulation of Sub-2 Nm Gold Nanoclusters for Cancer Radiation Therapy. Advanced Healthcare Materials 2014, 3 (1), 133-141. 3 Kulkarni, V. etc., Impact of ligand Structure on Biological Activity and Photophysical Properties of NHC-Protected Au13 Nanoclusters. J. Am. Chem. Soc 2025, 147 (5) 4017-4025. 4 Sullivan, A. etc. Diving into Unknown Waters: Water-Soluble Clickable Au13 Nanoclusters Protected with N-Heterocyclic Carbenes for Bio-Medical Applications. J. Am. Chem. Soc 2025, 147 (5) 4230-4238. Citation Format: Hetvi Shah, Angus Isaac Sullivan, Juan Chen, Gang Zheng. Atomically precise NHC-stabilized gold nanoclusters for enhanced photodynamic and X ray activated cancer therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6626.
Shah et al. (Fri,) studied this question.