Plasmonic Heterojunction Nanomaterials for Noninvasive Pan-Cancer Metabolomic Screening

Abstract

Cancer remains a major global health challenge, underscoring the urgent need for early diagnostic strategies. Altered cancer metabolism can be captured through serum analysis by laser desorption/ionization mass spectrometry (LDI-MS). Here, we report the design of gold nanoparticle-modified manganese–cobalt oxide heterojunctions (Au/MCOHs) as a high-performance LDI-MS nano-matrix. The Au/MCOHs combine strong ultraviolet absorption, enhanced charge separation, and favorable surface potential to achieve efficient laser energy conversion and ionization. Leveraging this platform, we performed serum metabolomic analysis on 698 participants, comprising healthy controls and patients with six different cancer types. Machine learning models distinguished cancer patients from healthy controls with area under the curve (AUC) values up to 0.955. Critically, early-stage cancers were also detected, with AUCs ranging from 0.776 to 0.938. Thirteen cancer-associated metabolites were identified, and a combined diagnostic panel achieved an AUC of 0.865. This study demonstrates how rationally engineered plasmonic heterojunction nanomatrices can bridge materials innovation and clinical translation, offering a robust, non-invasive route for pan-cancer metabolomic screening.

Keywords

early diagnosis / LDI-MS / pan-cancer / serum metabolic fingerprints

References

[1] F. Bray, M. Laversanne, H. Sung, et al., “Global Cancer Statistics 2022: Globocan Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA: A Cancer Journal for Clinicians 74, no. 3 (2024): 229–263.

[2] H. M. Bizuayehu, K. Y. Ahmed, G. D. Kibret, et al., “Global Disparities of Cancer and Its Projected Burden in 2050,” JAMA Network Open 7, no. 11 (2024): e2443198-e2443198.

[3] B. M. Lehrich, J. Zhang, S. P. Monga, and R. Dhanasekaran, “Battle of the Biopsies: Role of Tissue and Liquid Biopsy in Hepatocellular Carcinoma,” Journal of Hepatology 80, no. 3 (2024): 515–530.

[4] H. Zhang, L. Zhao, J. Jiang, et al., “Multiplexed Nanomaterial-Assisted Laser Desorption/Ionization for Pan-Cancer Diagnosis and Classification,” Nature Communications 13, no. 1 (2022): 617.

[5] J. Zhang, L. Xu, Y. Hu, et al., “Integrating Inertial Microfluidics With Sers Bioprobe for Efficient Enrichment and Accurate Identification of Tumor Cells in Gastric Fluid and Ascites,” Analytical Chemistry 97, no. 26 (2025): 13901–13911.

[6] Y. Tao, S. Xing, S. Zuo, et al., “Cell-Free Multi-Omics Analysis Reveals Potential Biomarkers in Gastrointestinal Cancer Patients' Blood,” Cell Reports Medicine 4, no. 11 (2023): 101281.

[7] World Health Organization, Guide to Cancer Early Diagnosis (World Health Organization, 2017).

[8] M. Shafer, V. Low, Z. Li, and J. Blenis, “The Emerging Role of Dysregulated Propionate Metabolism and Methylmalonic Acid in Metabolic Disease, Aging, and Cancer,” Cell Metabolism 37, no. 2 (2025): 316–329.

[9] D. Hanahan and R. A. Weinberg, “Hallmarks of Cancer: The Next Generation,” Cell 144, no. 5 (2011): 646–674.

[10] E. Holmes, A. Wijeyesekera, S. D. Taylor-Robinson, and J. K. Nicholson, “The Promise of Metabolic Phenotyping in Gastroenterology and Hepatology,” Nature Reviews Gastroenterology & Hepatology 12, no. 8 (2015): 458–471.

[11] C. Yang, H. Yu, W. Li, H. Lin, H. Wu, and C. Deng, “High-Throughput Metabolic Pattern Screening Strategy for Early Colorectal and Gastric Cancers Based on Covalent Organic Frameworks-Assisted Laser Desorption/Ionization Mass Spectrometry,” Analytical Chemistry 96, no. 16 (2024): 6264–6274.

[12] C. Yang, S. Ji, S. Shen, H. Yu, and C. Deng, “Advances in Nanomaterials Based Laser Desorption/Ionization Mass Spectrometry for Metabolic Analysis,” TrAC, Trends in Analytical Chemistry 186 (2025): 118190.

[13] Y. Liu, S. Yang, S. Li, et al., “Noble Metal Nanoparticle Assisted Mass Spectrometry for Metabolite-Based In Vitro Diagnostics,” Small 21, no. 4 (2025): 2409714.

[14] F. Shi, L. Chen, Y. Qiao, C. Deng, Q. Yao, and N. Sun, “Cross-Referencing Multifluid Metabolic Profiles on Hollow Dodecahedral Nanocages for Enhanced Disease Status Identification,” Small 21, no. 9 (2025): 2410638.

[15] X. Chen, Y. Wang, C. Pei, et al., “Vacancy-Driven High-Performance Metabolic Assay for Diagnosis and Therapeutic Evaluation of Depression,” Advanced Materials 36, no. 28 (2024): 2312755.

[16] F. Shi, J. Zhou, Y. Wu, et al., “In Vitro Diagnostic Examination and Prognosis Surveillance by Hierarchical Heterojunction-Assisted Metabolic Analysis,” Analytical Chemistry 94, no. 29 (2022): 10497–10505.

[17] J. Low, J. Yu, M. Jaroniec, S. Wageh, and A. A. Al-Ghamdi, “Heterojunction Photocatalysts,” Advanced Materials 29, no. 20 (2017): 1601694.

[18] H. Zhang, N. Li, F. Shi, et al., “Plasma Metabolic Profiles Via P-P Heterojunction-Assisted Laser Desorption/Ionization Mass Spectrometry for Advanced Warning and Diagnosis of Epidural-Related Maternal Fever,” Analytical Chemistry 96, no. 47 (2024): 18824–18833.

[19] C. Pei, Y. Wang, Y. Ding, et al., “Designed Concave Octahedron Heterostructures Decode Distinct Metabolic Patterns of Epithelial Ovarian Tumors,” Advanced Materials 35, no. 18 (2023): 2209083.

[20] Y.-H. Cheng and K.-M. Ng, “The Hidden Heroes: Holes in Charge-Driven Desorption Mass Spectrometry,” Analytical Chemistry 92, no. 8 (2020): 5645–5649.

[21] J. A. McLean, K. A. Stumpo, and D. H. Russell, “Size-Selected (2−10 nm) Gold Nanoparticles for Matrix Assisted Laser Desorption Ionization of Peptides,” Journal of the American Chemical Society 127, no. 15 (2005): 5304–5305.

[22] B. Shan, L. Li, Y. Zhao, H. Wang, and M. Li, “Near-Infrared II Plasmonic Au@Au–Ag Dot-in-Cubic Nanoframes for In Vivo Surface-Enhanced Raman Spectroscopic Detection and Photoacoustic Imaging,” Advanced Functional Materials 31, no. 29 (2021): 2103186.

[23] J. Qi, G. Chen, Z. Deng, et al., “Hierarchical Porous Microspheres-Assisted Serum Metabolic Profile for the Early Diagnosis and Surveillance of Postmenopausal Osteoporosis,” Analytical Chemistry 97, no. 1 (2025): 345–354.

[24] M.-J. Kim, T. G. Yun, J.-Y. Noh, et al., “Laser-Induced Surface Reconstruction of Nanoporous Au-Modified TiO₂ Nanowires for In Situ Performance Enhancement in Desorption and Ionization Mass Spectrometry,” Advanced Functional Materials 31, no. 29 (2021): 2102475.

[25] F. Zheng, Z. Yin, H. Xia, G. Bai, and Y. Zhang, “Porous MnO@C Nanocomposite Derived From Metal-Organic Frameworks as Anode Materials for Long-Life Lithium-Ion Batteries,” Chemical Engineering Journal 327 (2017): 474–480.

[26] X. Zhang, A. Yuan, X. Mao, Q. Chen, and Y. Huang, “Engineered Mn/Co Oxides Nanocomposites by Cobalt Doping of Mn-BTC—New Oxidase Mimetic for Colorimetric Sensing of Acid Phosphatase,” Sensors and Actuators B: Chemical 299 (2019): 126928.

[27] J. Cao, X. Shi, D. D. Gurav, et al., “Metabolic Fingerprinting on Synthetic Alloys for Medulloblastoma Diagnosis and Radiotherapy Evaluation,” Advanced Materials 32, no. 23 (2020): 2000906.

[28] H.-W. Tang, K.-M. Ng, W. Lu, and C.-M. Che, “Ion Desorption Efficiency and Internal Energy Transfer in Carbon-Based Surface-Assisted Laser Desorption/Ionization Mass Spectrometry: Desorption Mechanism(s) and the Design of Saldi Substrates,” Analytical Chemistry 81, no. 12 (2009): 4720–4729.

[29] S. K.-M. Lai, H.-W. Tang, K.-C. Lau, and K.-M. Ng, “Nanosecond UV Laser Ablation of Gold Nanoparticles: Enhancement of Ion Desorption by Thermal-Driven Desorption, Vaporization, or Phase Explosion,” Journal of Physical Chemistry C 120, no. 36 (2016): 20368–20377.

[30] W. E. Johnson, C. Li, and A. Rabinovic, “Adjusting Batch Effects in Microarray Expression Data Using Empirical Bayes Methods,” Biostatistics 8, no. 1 (2006): 118–127.

[31] N. V. Chawla, K. W. Bowyer, L. O. Hall, and W. P. Kegelmeyer, “Smote: Synthetic Minority Over-Sampling Technique,” Journal of Artificial Intelligence Research 16 (2002): 321–357.

[32] M. Arnold, C. C. Abnet, R. E. Neale, et al., “Global Burden of 5 Major Types of Gastrointestinal Cancer,” Gastroenterology 159, no. 1 (2020): 335–349.e15.

[33] T. A. Ullman and S. H. Itzkowitz, “Intestinal Inflammation and Cancer,” Gastroenterology 140, no. 6 (2011): 1807–1816.e1.

[34] T. L. Cover and M. J. Blaser, “Helicobacter Pylori in Health and Disease,” Gastroenterology 136, no. 6 (2009): 1863–1873.

[35] D. Crosby, S. Bhatia, K. M. Brindle, et al., “Early Detection of Cancer,” Science 375, no. 6586 (2022): eaay9040.

[36] P. Cavuoto and M. F. Fenech, “A Review of Methionine Dependency and the Role of Methionine Restriction in Cancer Growth Control and Life-Span Extension,” Cancer Treatment Reviews 38, no. 6 (2012): 726–736.

[37] Z. Wang, L. Y. Yip, J. H. J. Lee, et al., “Methionine Is a Metabolic Dependency of Tumor-Initiating Cells,” Nature Medicine 25, no. 5 (2019): 825–837.

[38] O. Mortusewicz, J. Haslam, H. Gad, and T. Helleday, “Uracil-Induced Replication Stress Drives Mutations, Genome Instability, Anti-Cancer Treatment Efficacy, and Resistance,” Molecular Cell 85, no. 10 (2025): 1897–1906.

[39] N. J. Mullen and P. K. Singh, “Nucleotide Metabolism: A Pan-Cancer Metabolic Dependency,” Nature Reviews Cancer 23, no. 5 (2023): 275–294.

[40] E. J. Fine, A. Miller, E. V. Quadros, J. M. Sequeira, and R. D. Feinman, “Acetoacetate Reduces Growth and ATP Concentration in Cancer Cell Lines Which Over-Express Uncoupling Protein 2,” Cancer Cell International 9, no. 1 (2009): 14.

[41] E. L. Lieu, T. Nguyen, S. Rhyne, and J. Kim, “Amino Acids in Cancer,” Experimental & Molecular Medicine 52, no. 1 (2020): 15–30.

[42] L. Zhang and P. Bu, “The Two Sides of Creatine in Cancer,” Trends in Cell Biology 32, no. 5 (2022): 380–390.

[43] J. M. Loo, A. Scherl, A. Nguyen, et al., “Extracellular Metabolic Energetics Can Promote Cancer Progression,” Cell 160, no. 3 (2015): 393–406.

[44] V. R. Jala, S. R. Bodduluri, S. R. Satpathy, Z. Chheda, R. K. Sharma, and B. Haribabu, “The Yin and Yang of Leukotriene B₄ Mediated Inflammation in Cancer,” Seminars in Immunology 33 (2017): 58–64.

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