Engineering the microenvironment: advanced biomaterials for humanized in vitro immunotoxicology and carcinogenicity assessment

The challenges of conventional animal models and two-dimensional (2D) in vitro cell cultures in effectively forecasting human toxicity have prompted a significant shift towards New Approach Methodologies (NAMs). This development centers on advanced humanized in vitro co-culture models that offer improved physiological relevance for toxicological assessment. This perspective highlights the critical role of biomaterials in the creation of complex microenvironments. This study demonstrates how biomaterials effectively mimic the original extracellular matrix (ECM) through controlled compositional, structural, mechanical, and biochemical signals, thereby enabling the development of sophisticated 3D spheroids, organoids, and Organ-on-Chip systems. These biomaterial-enhanced platforms are essential for precise evaluation of immunotoxicity, as they promote human-specific immune responses and targeted immunomodulation, and for carcinogenicity, as they accurately replicate the tumor microenvironment, affect cancer cell behavior, and enable patient-derived models. Moreover, we underscore the synergistic amalgamation of these biomaterial-based models with omics technologies and computational methodologies (QSAR, AI/ML) for thorough molecular insights and rational design. Despite ongoing challenges in standardization and high-throughput compatibility, the strategic utilization of biomaterials is set to transform predictive toxicology, expedite drug discovery, and promote personalized medicine, thereby diminishing dependence on animal testing and improving human safety.