Efferocytosis-Mimicking Nanovesicle-Cross-Linked Hydrogel for Dual Immunomodulation and Angiogenesis to Prolong Allogeneic Skin Graft Survival.

Abstract

Sustained local immunosuppression and angiogenesis to prolong graft survival remain elusive goals in allogeneic transplantation. Biomimcking natural efferocytosis to synchronously recruit and regulate endogenous regulatory T cells (Tregs), anti-inflammatory M2 macrophages, and vascular endothelial cells at the transplantation site provides a strategy to address these challenges. While macrophages and endothelial cells, as phagocytes, can be modulated through efferocytosis; T cells, being nonphagocytes, lack this capability. Herein, we developed an efferocytosis-mimicking nanovesicle-cross-linked hydrogel (EMV-Gel) that functions as a sustainably localized "efferocytosis reservoir" at the transplantation site. This gel releases high intensity of key efferocytosis signals, including "find-me", "eat-me", and apoptotic metabolite signals, thereby facilitating the recruitment and engulfment of T cells, macrophages, and endothelial cells, achieving sustained and simultaneous vascular regeneration alongside the induction of Tregs and M2 macrophages. This work establishes a pro-regenerative niche that orchestrates both vascular remodeling and sustained immunosuppression, prolonging allogeneic skin graft survival.