The biointerface at the surface of LNPs, comprising the surface lipids identified here and bioadsorbate molecules from the biological milieu in service, is thin and can therefore be regarded as an ideal opportunity for calibration of SIMS for quantification since the matrix effect may be controllable. It has been has shown that in model organic systems the matrix effect is insignificant for thickness < 5 nm. Furthermore, undertaking the analysis in frozen hydrated state is analogous to implantation of oxygen in semiconductors where SIMS is routinely used to quantify dopants, by implanting oxygen to 'normalise' the matrix, providing opportunity for quantification in future. Importantly, the presence of frozen hydrated water also increases the sensitivity to many species compared to dehydrated samples by up to ×10,000. Using standard mixtures to map the relationship between Orbitrap counts, secondary ion yield (counts/nm 3 ) and molar molecular concentrations, may allow biointerface molecular quantification, so long as sufficiently large sets of calibration data can be generated and appropriately analysed to produce useful sensitivity factors and to monitor for matrix effects. Control of salts and characterisation of their effects in such calibration datasets will be important since they are unavoidable for real-world samples in vitro and in vivo.