Mechanical forces from intercellular peptide self-assembly drive spheroid formation.

This work presents a general strategy for engineering cell spheroids with capillary-like structures using intercellular self-assembly of peptide nanofibers. These nanofibrous materials induce mechanical changes in the extracellular matrix (ECM), activate mechanotransduction pathways, and enhance cellular morphogenesis, resulting in dynamic 3D spheroids with improved cell-cell and cell-matrix interactions. By promoting the formation of capillary-like structures within tumor spheroids, we develop models that closely mimic human tissue physiology. Our results demonstrate that tumor spheroids with capillary-like structures display gene expression profiles that closely match those of patient-derived tumors, underscoring their relevance for cancer research. Furthermore, these spheroids, including those derived from an islet cell line, exhibit significantly increased functionality, such as enhanced insulin secretion in response to glucose stimulation, highlighting their potential for diabetes research and regenerative medicine applications. This work advances our understanding of tissue engineering and provides a robust platform for studying complex cellular interactions and therapeutic responses. By highlighting the critical role of capillary-like structure formation in engineered tissues, our findings pave the way for innovative strategies to address significant challenges in drug delivery and cancer therapy, ultimately enhancing patient care and treatment outcomes.