Xenoextracellular matrix-rosiglitazone complex-mediated immune evasion promotes xenogenic bioengineered root regeneration by altering M1/M2 macrophage polarization

Xenogenic extracellular matrix (xECM)-based organ transplantation will be a promising approach to address the problem of donor shortage for allotransplantation, which has achieved great success in organ regeneration. However, current approaches to utilize xECM-based organ have limited capacity to yield the host a biofriendly microenvironment for long-term immunity homeostasis, compromising the application of these xenografts for repairing and replacing damaged tissues. As the key innate immune cells, macrophages directly determine the prognosis of xenografts in long term. However, it has not been fully elucidated that how to modulate their biological behavior for microenvironment homeostasis in tissue reconstruction. In this study, we report a robust strategy to impart an immunosuppressive surface to naturally sponge-like porous xECM scaffolds by loading rosiglitazone (RSG) to activate peroxisome proliferators receptors-γ (PPAR-γ). The resultant xECM-RSG complex, enabling RSG to be delivered sequentially and continuously to cells without obvious systemic side effects, is recognized as "self" to escape immune monitoring in local immunoregulation by downregulating the expression of proinflammatory NOS2+ M1 macrophages and oxygen species (ROS) through suppressing NF-κB expression, greatly facilitating the regeneration of enthesis anchoring between the transplanted xenograft and host in both heterotopic and orthotopic models. The newly formed bio-root is morphologically and biomechanically equivalent to native tooth root with a significant expression of odontogenic differentiation-related critical proteins. Therefore, the PPAR-γ-NF-κB axis activated by the xECM-RSG complex enables the xenografts to converse towards M2 macrophages with a modest immunosuppressive capacity for facilitating in xECM-based tissue or organ regeneration.