Chirality‐Encoded Biomaterials Regulate Local and Systemic Immune Responses in Transplantation

Biomaterial-based immune modulation offers an opportunity to achieve localized graft acceptance without systemic immunosuppression. Here, we demonstrate that molecular chirality within microporous annealed particle (MAP) hydrogels governs innate and adaptive immune responses in skin transplantation and is associated with modulation of alloimmune outcomes. By engineering injectable MAP scaffolds composed of microgels crosslinked with L- or D-peptides, we show that chirality directs early antigen-presenting cell (APC) activation and trafficking in draining lymph nodes, leading to distinct T cell polarization profiles. A mixed-chirality formulation (R-MAP) composed of L- and D-microgels is associated with reduced APC co-stimulatory signaling (MHC II, CD80, CD86) and preserves graft architecture and tissue integration in syngeneic transplants. In fully allogeneic skin grafts, local mixed-chirality MAP implantation is associated with reduced donor-specific antibody (DSA) formation and attenuated antimaterial and antidonor IgG responses, achieving sustained attenuation of humoral alloimmunity within the experimental conditions studied. These findings establish stereochemical control of biomaterial composition as a design principle for modulating APC-T-B cell crosstalk, linking local material cues to systemic immune outcomes. Mixed-chirality MAP scaffolds thus provide a versatile platform for spatially confined, chirality-guided immunomodulation, with implications for transplantation, regenerative medicine, and biomaterial-driven tolerance strategies.