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This combined hyperspectral and NIR-II imaging platform provides cellular-level detection of deep-tissue biological features in vivo. This allows for the detection of small numbers of cells at early stages of disease, rendering the system applicable for early diagnostics (e.g., of cancers or infectious disease), leading to better patient response to therapy and increased chances of remission. The system is also capable as a real-time surgical assistance tool that can minimize residual disease, thus improving patient prognosis and long-term survival rates. Patient response to therapy can be monitored at the cellular level. Furthermore, the system provides the capability to phenotype cancers with increased sensitivity, promoting the creation of personalized treatment plans to maximize efficiency.