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4.1. spheroids and organoidsTumor spheroids have been widely used as 3D models for nanotherapiesscreening, providing a more accurate representation of the tumormicroenvironment compared to 2D cell cultures. These microscale,spherical cell clusters formed through self-assembly, are one of the mostcommon and versatile methods of 3D cell culture. Spheroids are highlyversatile and depending on their size they can recapitulate proliferationregions on the outside and quiescent or necrotic regions on the inside dueto nutrient and oxygen transport limitations, similar to those observed inmany cancers in vivo. Over the past decade, numerous studies have explored nanoparticlemediated drug delivery and drug uptake using tumor spheroid models,particularly in lung, colorectal, and ovarian cancers. For instance, is arecent study where the researcher explored the potential of repurposingamodiaquine (AQ), an antimalarial drug, for the treatment of non-small celllung cancer (NSCLC). The researchers developed inhalable nanoparticlescontaining AQ using a scalable high-pressure homogenization (HPH) process.The authors employed 3D spheroids of A549 and H1299 cell lines to furtherexamine the nanoparticle%u2019s penetration and growth-inhibiting properties,and the outcomes demonstrate great potential. The work emphasizes howdrug repurposing in cancer nanomedicine has promise for creating noveltherapeutics with possibly shorter development times and cheaper coststhan conventional drug discovery methods. In more advanced work,researchers also applied a similar nanotherapies technology in thedevelopment of a targeted drug delivery system for ovarian cancertreatment by combining photothermal nanoparticle-based therapy withtumor spheroids. The bioengineering of the spheroids was based on the useof hydrogel microwell arrays that enable the production of structurally welldefined 3D tumor spheroids, in a high-throughput way. The findings showedthe capacity of the developed system in the production of robust 3Dspheroids, that can be easily transferable to 2D culture substrates whilemaintaining their 3D structure. To validate the ability of these models torecapitulate the in vivo scenario of the tumors, gold-graphene hybridnanoparticles were loaded with doxorubicin and were integrated in themodel for photothermal cancer therapy. The results demonstratedselectivity of the nanoparticles towards fast-dividing cells in 3D spheroids. In the last few years organoids and tumoroids have emerged as modelsfor cancer research, offering a more complex architecture and cellcomposition recapitulating more closely the native primary tumor tissue.Organoids can be derived from human stem cells, organ-specific progenitor114Potential of 3D tumor models for nanotherapies pre-clinical screeningVitor M. Gaspar1, Jo%u00e3o F. Mano, et al.