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This paper presents a significantly improved quartz crystal microbalance (QCM) with sub-picogram mass sensing resolution in liquid while maintaining a high quality factor (Q) without much loss. Our design removes the liquid damping effect through an acoustic loss isolation layer (vacuum) and a sensing diaphragm, which reduce the direct contact area at the interface between the QCM and liquid. The vacuum-gapped QCM turns out to have a very high resonant Q in liquid of 196,340, only a 13.2% reduction from the Q in air. The device sensitivity is 6 cm2/g, corresponding to a remarkably high mass resolution of 90 fg/cm2 in liquid.