Rational design of immunological programs for functional regenerative niches

The immune system is a master conductor of tissue repair, yet its therapeutic potential remains underexploited. Moving beyond descriptive biology, we propose ‘immunoprogramming’ as an active design paradigm that synergistically integrates stem cells and biomaterials to steer host immunity toward pro-regenerative outcomes. Here, we decode the source-specific immunomodulatory signatures of stem cells—from bone marrow and adipose tissue to dental and iPSC-derived populations—and establish how the biochemical and biophysical language of engineered biomaterials can directly command innate and adaptive immune cell fate. Crucially, we emphasize that within integrated cell-scaffold constructs, a bidirectional crosstalk emerges: the biomaterial primes the stem cell, which in turn execute enhanced context-specific immunomodulation. To translate this synergy into a design discipline, we introduce the Synergistic Immuno-Instructional System (SIIS) framework, which modularizes Cell-Source-Specific Immuno-Modules (CSIMs), Biomaterial-Based Immuno-Code (BIC), and Tissue-Specific Immuno-Niche (TSIN). Finally, we discuss translational challenges and advocate for next generation ‘immuno-informed’ therapeutics that evolve from passive replacement to active immune niche engineering, charting a course for intelligent regenerative medicine.