Engineering immune niches: biochemical, mechanical, and spatial design principles for translational hydrogels.

Leveraging advanced materials is an increasingly important direction in immune engineering, which aims to reprogram immune responses to treat disease. Once implanted, biomaterials rapidly become sites where immune cells assemble, interact, and collectively shape material performance. These organized multicellular environments, or immune niches, are linked to outcomes ranging from tissue regeneration to durable immune memory, yet the principles governing their formation and function remain poorly understood. In this Mini-Review, we examine how engineered translational hydrogels act both as modulators of immune niches and as tractable in vivo model systems for studying them. We highlight how biochemical cues such as antigens, adjuvants, cytokines, and chemokines control which cells enter a niche and how they become activated, and how biophysical properties including stiffness, viscoelasticity, porosity, and degradability influence cellular access, motility, and phenotype. Adhesion motifs are discussed as a hybrid class of signals that couple biochemical recognition to mechanical force transmission. We also describe how emerging spatial and multi-omic technologies are beginning to reveal the architecture and communication networks that define hydrogel-associated niches. Future progress will require close collaboration between materials scientists, immunologists, and computational biologists to establish the design principles needed to engineer immune niches that improve therapeutic outcomes. Graphical Abstract: