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Abstract Photoacoustic tomography offers a powerful tool to visualize biologically relevant molecules and understand processes within living systems at high resolution in deep tissue, facilitated by the conversion of incident photons into low-scattering acoustic waves through non-radiative relaxation. Although current endogenous and exogenous photoacoustic contrast agents effectively enable molecular imaging within deep tissues, their broad absorption spectra in the visible to near-infrared (NIR) range limit photoacoustic multiplexed imaging. Here, we exploit the distinct ultrasharp NIR absorption peaks of lanthanides to engineer a series of NIR photoacoustic nanocrystals. This engineering involves precise host and dopant material composition, yielding nanocrystals with sharply peaked photoacoustic absorption spectra (~3.2 nm width) and a ~10-fold enhancement in NIR optical absorption for efficient deep tissue imaging. By combining photoacoustic tomography with these engineered nanocrystals, we demonstrate photoacoustic multiplexed differential imaging with substantially decreased background signals and enhanced precision and contrast.