Enhanced Photoacoustic Detection of Heparin in Whole Blood <i>via</i> Melanin Nanocapsules Carrying Molecular Agents.

Photoacoustic (PA) imaging has proved versatile for many biomedical applications from drug delivery tracking to disease diagnostics and postoperative surveillance. It recently emerged as a tool for accurate and real-time heparin monitoring to avoid bleeding complications associated with anticoagulant therapy. However, molecular-dye-based application is limited by high concentration requirements, photostability, and a strong background hemoglobin signal. We developed polydopamine nanocapsules (PNCs) <i>via</i> supramolecular templates and loaded them with molecular dyes for enhanced PA-mediated heparin detection. Depending on surface charge, the dye-loaded PNCs undergo disassembly or aggregation upon heparin recognition: both experiments and simulation have revealed that the increased PA signal mainly results from dye-loaded PNC-heparin aggregation. Importantly, Nile blue (NB)-loaded PNCs generated a 10-fold higher PA signal than free NB dye, and such PNC enabled the direct detection of heparin in a clinically relevant therapeutic window (0-4 U/mL) in whole human blood (<i>R</i>² = 0.91). Furthermore, the PA signal of PNC@NB obtained from 17 patients linearly correlated with ACT values (<i>R</i>² = 0.73) and cumulative heparin (<i>R</i>² = 0.83). This PNC-based strategy for functional nanocapsules offers a versatile engineering platform for robust biomedical contrast agents and nanocarriers.