The development of lanthanide-doped upconversion nanoparticle (UCNP)-based imaging with minimal autofluorescence and improved penetration depth is important in medical applications. Exogenous nanocarriers readily adsorb plasma proteins following intravenous administration (<
0.5 min), resulting in the formation of a protein corona on the fixed surface. The protein corona facilitates UCNP interception by the immune system, preventing targeted delivery to disease sites. In this study, we report a novel surface-camouflaging strategy using lanthanide hydroxyl carbonate that is slowly dissolved by physiological phosphate in serum. The "self-consuming" inorganic-shell-modified UCNPs (denoted as UCSP-PEG) effectively reduce protein corona adhesion by more than 90% through a dissociation effect associated with the amphiphilic poly(ethylene glycol) (PEG)-modified UCNPs as determined in an ex vivo assay. The UCSP-PEG exhibits a prolonged blood circulation time (