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nanotherapeutics that are functionalized with multivalent tumor targetingmoieties or created with certain physicochemical qualities to overcomethese restrictions. Nevertheless, it has been difficult and expensive toassess the best trade-off between ligand selectivity, surface density, surfacepassivation by protein corona-mediated changes, and nanomedicinestability in biological environments.In light of the significant shifts in cell culture techniques, the in vitroscreening of nanotherapies has shifted from conventional 2D cultures to 3Dmodels (such as spheroids) and even on-chip systems. The implementationand testing of such therapeutics in 3D cell cultures offers several significantadvantages for cancer research and drug development. For example, thesemodels provide a better and more physiologically relevant model toevaluate the nanoparticles penetration and distribution within the tumorvolume, which is crucial for understanding the effectiveness ofnanotherapies. In the following sub-sections, a comprehensive overview ofthe different 3D models used. 113 Nanomaterial y NanomedicinaMar%u00eda Vallet , Antonio J. Salinasfigure 1. Potential of 3D in vitro tumor models for accelerating and upgrading nanotherapiesscreening for cancer treatment. 3D tumor models enable researchers to better recapitulate thecomplex native tumor-microenvironment more accurately than monolayer cultures. suchplatforms offer the ability to evaluate for example the impact of natural physiological barriersto nanotherapeutics penetration and the delivery/internalization to cancer cells (or others ofthe stromal compartment), as well as their performance and therapeutic efficacy. Theseadvancements in the preclinical validation of nanotherapeutics contribute to largely reducinganimal models%u2019 usage, being in line with the most recent guidelines from regulatory organizations(i.e., fDA, etc.). Illustration prepared with bioRender software.%u00a0