Biomaterial design increasingly considers how adaptive immunity influences tissue regeneration, yet most efforts have focused on T lymphocyte responses. Here, we show that D-chiral Microporous Annealed Particle (DMAP) scaffolds promote dermal appendage regeneration through engagement of humoral immunity. In a splinted full-thickness wound model, DMAP supported regeneration even when lymphocyte infiltration was restricted, indicating that infiltrating adaptive immune cells are not strictly required. Instead, DMAP activated B cells in the skin draining lymph nodes, driving germinal center formation and the production of biomaterial-specific antibodies alongside pro-regenerative systemic factors. This circulating milieu was sufficient to confer regenerative healing in wounds treated with biomaterials that promote collagen repair but not hair follicle regeneration. Together, these findings establish humoral immunity as a central component of biomaterial-induced regeneration and highlight new opportunities to harness systemic factors for tissue repair.
