In-vitro metabolite detection relies on designed materials based analytical platforms and is universally employed in biomedical research and clinical practice. However, metabolite analysis in bio-samples always need tedious pre-treatment, due to the sample complexity and low molecular abundance. What is more challenging is to construct diagnostic tools by materials based platforms. Herein, we developed several novel platforms using plasmonic nanoshells. We synthesized SiO2@Ag and SiO2@Au with tunable shell structures using both chemical and physical method. Optimized nanoshells facilitated metabolome fingerprinting in 0.5 μL of bio-fluids by direct laser desorption/ionization mass spectrometry. We applied these nanoshells for disease diagnosis and therapeutic evaluation. We identified patients with postoperative brain infection through daily monitoring and glucose quantitation in cerebrospinal fluid (CSF). We measured drug distribution in blood and CSF systems and validated the function of blood-brain/CSF-barriers for pharmacokinetics. Our work sheds light on the design of nanomaterials for advanced metabolite analysis and precision diagnostics.