Engineered biomaterials have great versatility in addressing disease conditions, with applications ranging from drug delivery to engineered implants. However, an outstanding question remains whether the underlying patient disease can impact the body’s response to these engineered materials and, if so, how new materials can be designed to account for this underlying heterogeneity. In my work, I present two parallel approaches to address this outstanding question: first by studying the impact of gut microbiome-mediated metabolic syndrome effect on engineered vaccines and next, by developing modular hydrogel organoid platform to grow patient-derived prostate tumors and study the role of disease heterogeneity on cancer progression, mechanotransduction and signaling pathways, and therapeutic outcomes.