Development of Silica Nanoparticles Embedded Adipose Spheroid Platform for Probing Bacteriophage Sequestration and Its Implications for Phage Therapy

We engineer an enhanced three-dimensional (3D) adipose model by integrating mesoporous silica (mSiO2) nanoparticles into human adipose-derived stem cell spheroids. The mSiO2 is highly cytocompatible, enables stable dispersion, and yields spheroids that preserve structural integrity and roundness for at least 14 days, accompanied by higher metabolic activity and reduced hypoxic stress. Under adipogenic induction, the nanoparticles embedded spheroids exhibit deeper lipid accumulation and increased expression of PPARγ, adiponectin, and FABP4. As a proof of concept, we leveraged this 3D platform to examine phage uptake and tissue-level distribution in adipose spheroids in comparison with conventional 2D cultures. These experiments reveal that both the cellular differentiation state and the tissue architecture govern phage association and uptake. Together, our findings indicate that phages engage mammalian cells beyond their bacterial hosts, a consideration that should inform future phage therapy design with implications for innate immune responses and overall therapeutic efficacy.