For the roughly two million people living with type 1 diabetes globally, the immune system is both cause and obstacle — destroying beta cells first and then attacking any transplanted replacement tissue. A convergence of genome engineering and advanced biomaterials is now rewriting the rules of islet transplantation, potentially decoupling curative cell therapy from the toxicity of lifelong immunosuppression.
This review, published in Biomaterials Science, maps the evolving landscape of immune-evasion strategies for transplanted islets — both donor-derived and stem cell-generated. The authors organize approaches along two axes: cell-intrinsic modifications, where the islet itself is re-engineered to evade immune detection, and peri-graft strategies, which reshape the local microenvironment surrounding the transplant. On the intrinsic side, CRISPR-Cas9 editing occupies center stage, enabling targeted disruption of MHC class I surface antigens, upregulation of immune checkpoint ligands such as PD-L1, and silencing of pro-inflammatory signaling nodes — moves designed to render grafts invisible or actively tolerogenic to host immune cells. Complementing permanent edits, transient RNA interference and mRNA-based gene silencing offer tunable, reversible immune programming. On the peri-graft side, hydrogel encapsulants, localized drug-eluting scaffolds, and bioactive coatings are being engineered to blunt innate inflammatory cascades and recruit regulatory immune populations at the graft site.
Placing this work in broader context, it arrives at a moment of genuine clinical momentum: Vertex Pharmaceuticals' VX-880 stem cell-derived islet program recently produced sustained insulin independence in early-phase human trials, validating the therapeutic premise but also exposing the persistence of immune-mediated graft attrition even under aggressive immunosuppression. The dual-pronged strategy reviewed here — editing the cell and conditioning its niche — represents a logical and potentially synergistic response to that limitation. Key caveats remain substantial: most CRISPR immune-evasion data derive from rodent xenograft models, manufacturing complexity is formidable at clinical scale, and the long-term oncogenic or off-target risk of permanent genome edits in transplanted cells has not been fully characterized. This is a rapidly maturing field rather than a solved problem, but the convergence of precision gene editing with sophisticated biomaterial engineering marks a qualitative shift in ambition and feasibility.