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Maaike VJ Braham,1 Anil K Deshantri,2,3 Monique C Minnema,4 F Cumhur Öner,1 Raymond M Schiffelers,2 Marcel HAM Fens,2,5 Jacqueline Alblas1 1Department of Orthopaedics, University Medical Center Utrecht, Utrecht, the Netherlands; 2Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands; 3Department of Pharmacology, Sun Pharma Advanced Research Company Limited, Vadodara, Gujarat, India; 4Department of Hematology, University Medical Center Utrecht Cancer Center, Utrecht, the Netherlands; 5Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands Purpose: Liposomal drug delivery can improve the therapeutic index of treatments for multiple myeloma. However, an appropriate 3D model for the in vitro evaluation of liposomal drug delivery is lacking. In this study, we applied a previously developed 3D bone marrow (BM) myeloma model to examine liposomal drug therapy. Material and methods: Liposomes of different sizes (~75–200 nm) were tested in a 3D BM myeloma model, based on multipotent mesenchymal stromal cells, endothelial progenitor cells, and myeloma cells cocultured in hydrogel. The behavior and efficacy of liposomal drug therapy was investigated, evaluating the feasibility of testing liposomal drug delivery in 3D in vitro. Intracellular uptake of untargeted and integrin α4β1 (very late antigen-4) targeted liposomes was compared in myeloma and supporting cells, as well as the effectivity of free and liposome-encapsulated chemotherapy (bortezomib, doxorubicin). Either cocultured myeloma cell lines or primary CD138+ myeloma cells received the treatments. Results: Liposomes (~75–110 nm) passively diffused throughout the heterogeneously porous (~80–850 nm) 3D hydrogel model after insertion. Cellular uptake of liposomes was observed and was increased by targeting very late antigen-4. Liposomal bortezomi