Metal−organic frameworks (MOFs) represent an attractive family of materials for diverse biomedical applications due to their porosity, chemical versatility, and stimuli-responsive properties. Next to their drug delivery and bioimaging applications, MOFs have been recently considered as efficient luminescent thermal probes. However, the relatively low thermal sensitivity together with the biocompatibility of most MOF thermometers limits their practical applications. Here, a series of new MOFs based on Zn ions and a rectangular tetratopic ligand H4TBAPy (1,3,6,8-tetrakis(p-benzoic acid)pyrene) is reported, demonstrating a temperature-dependent photoluminescence (PL) with up to 2.12% K−1 relative thermal sensitivities over the 7 – 300 K temperature range. Using a topological design approach, the structure of the obtained MOFs is tuned from two- to three-dimensions via solvent exchange in order to build the optimal structure of the PL thermometer. Then, the resulting MOFs have been exfoliated to obtain MOF nanosheets (NSs) to be easily injected into living organisms. As a result, MOF NSs, intracardiac injected or introduced into the digestive system of the Casper fish, reveal a 100% survival rate together with an efficient in vivo PL thermometry of organs, thereby, paving the way to a rational design of highly sensitive and biocompatible MOF-based thermometers.