Gold-siRNA supraclusters enhance the anti-tumor immune response of stereotactic ablative radiotherapy at primary and metastatic tumors | Nature Biotechnology

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Strategies to enhance the anti-tumor immune response of stereotactic ablative radiotherapy (SABR) at primary tumors and abscopal sites are under intensive investigation. Here we report a metabolizable binary supracluster (BSCgal) that combines gold nanoclusters as radiosensitizing adjuvants with small interfering RNA (siRNA) targeting the immunosuppressive mediator galectin-1 (Gal-1). BSCgal comprises reversibly crosslinked cationic gold nanoclusters and siRNA complexes in a polymer matrix that biodegrades over weeks, facilitating clearance (90.3% in vivo clearance at 4 weeks) to reduce toxicity. The particle size well above the renal filtration threshold facilitates passive delivery to tumors. Using mouse models of head and neck cancer, we show that BSCgal augments the radiodynamic and immunotherapeutic effects of SABR at the primary and metastatic tumors by promoting tumor-inhibitory leukocytes, upregulating cytotoxic granzyme B and reducing immunosuppressive cell populations. It outperforms SABR plus Gal-1 antagonists, chemoradiation drug cisplatin or PD-1 inhibitor. This work presents a translatable strategy to converge focal radiosensitization with targeted immune checkpoint silencing for personalized radioimmunotherapy.

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All data supporting this study’s findings are provided in the article and Supplementary Information. Additional technical details can be obtained from the corresponding author upon reasonable request. Source data are provided with this paper.

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This study was supported by the following grants: P01CA257907 (to Q.T.L., E.E.G., Y.J., H.C., H.D., L.G. and J.L.) from the National Cancer Institute, R01DE029672 (to Q.T.L, Y.J., H.C., H.D., L.G. and J.L.) from the National Institute of Dental and Craniofacial Research and U54CA274511 (to Q.T.L.) from the National Cancer Institute of the National Institutes of Health. Schematic illustrations were created using BioRender. The anti-galectin-1 blocking antibody (aGal-1) was generously provided by Bristol Myers Squibb via a material transfer agreement.

Department of Radiation Oncology, Stanford University, Stanford, CA, USA

Yuyan Jiang, Hongbin Cao, Huaping Deng, Li Guan, Jimpi Langthasa, Stavros Melemenidis, Edward E. Graves, Anusha Kalbasi & Quynh-Thu Le

Department of Pathology, Stanford University, Stanford, CA, USA

Deana Rae Crystal Colburg

Department of Comparative Medicine, Stanford University, Stanford, CA, USA

Renee M. Cotton

Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA

John Aleman

Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA

Xiao-Jing Wang

Veterans Affairs Northern California Health Care System, Mather, CA, USA

Xiao-Jing Wang

School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore

Kanyi Pu

Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

Kanyi Pu

Department of Chemistry, Stanford University, Stanford, CA, USA

Jianghong Rao

Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, USA

Jianghong Rao

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Y.J. and Q.-T.L. conceived the study. Y.J. developed supraclusters and performed in vitro characterization. Y.J., H.C. and L.G. conducted cell experiments. Y.J., H.C., H.D., J.L. and R.M.C. conducted animal experiments. Y.J., H.C. and L.G. conducted flow cytometry analyses. X.-J.W. and J.A. shared P029 cell lines and laboratory resources. Y.J. and S.M. conducted whole-animal perfusion. D.R.C.C. conducted IHC and IF staining. Y.J. and J.R. designed the in vivo clearance study and experiments on abscopal effect. E.E.G. and Y.J. developed the SABR treatment protocol. Q.T.L. supervised the project. J.R., K.P. and A.K. contributed to instructing this project. Y.J., Q.-T.L., J.R., K.P. and A.K. contributed to editing of the manuscript.

Correspondence to Quynh-Thu Le.

Y.J. and Q.-T.L. are named inventors on a patent application related to the metabolizable supraclusters and their use in cancer treatments, which are described in this work. The other authors declare no competing interests.

Nature Biotechnology thanks Joe Y. Chang, Xiaoyuan Chen, Arta Monir Monjazeb and Jianping Xie for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

(a) ROS production in MOC2 cells after incubation with PBS, GSC (50 μg/mL), or BSCgal (50 μg/mL) followed by RT (6 Gy). ROS was indicated by green fluorescence from H2DCFDA probe. Scale bar, 100 μm (b) Mean fluorescence intensity (MFI) of ROS production in MOC2 cells after various treatments (RT = 6 Gy; n = 5, biologically independent replicates). Data were presented as mean ± SD. Comparison among PBS, GSC and BSCgal was determined by one-way ANOVA (P = 0.7288). The others were analyzed by two-tailed unpaired Student’s t-test. ns, not statistically significant; ns P (BSCgal + RT vs GSC + RT) = 0.7109; ****P < 0.0001. (c) Clonogenic survival assay of MOC2 cells various treatments (n = 3). P value was determined by two-tailed unpaired Student’s t-test. *P = 0.0137; **P = 0.005. Data were expressed as mean ± SD.

(a) Quantification of CRT fluorescence intensity in Fig. 5b (n = 5). ***P = 0.0006; ****P < 0.0001. (b) HMGB1 concentration in the plasma of mice after various treatments (n = 5). **P (GSC + SABR vs PBS + SABR) = 0.0038, **P (BSCgal + SABR vs BSCgal) = 0.003, *P (BSCgal + SABR vs PBS + SABR) = 0.0304. (c) Box plot of percentage of GzmB+ cells in tumor-infiltrating CD8+ T cells from mice after various treatments (n = 5). *P = 0.0458; **P = 0.0066; ***P = 0.0002. (d) Box plot of percentage of Ki67+CD8+ T cells in tumor- infiltrating CD45+ leukocytes from mice after various treatments (n = 5). *P = 0.0319; **P (BSCgal vs GSC) = 0.0045; **P (BSCgal + SABR vs BSCgal) = 0.0082. In (a-b), comparison among PBS, GSC and BSCgal was determined by one-way ANOVA. The other P values were determined by two-tailed unpaired Student’s t-test. ns, not statistically significant (P > 0.05).

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Unprocessed western blots.

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Jiang, Y., Cao, H., Deng, H. et al. Gold-siRNA supraclusters enhance the anti-tumor immune response of stereotactic ablative radiotherapy at primary and metastatic tumors. Nat Biotechnol (2024). https://doi.org/10.1038/s41587-024-02448-0

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Received: 01 February 2024

Accepted: 24 September 2024

Published: 24 October 2024

DOI: https://doi.org/10.1038/s41587-024-02448-0

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