Photoactivatable Exosenolytics Activate Natural Killer Cells for Delaying Osteoarthritis

Abstract

Osteoarthritis (OA) is a classic age-related disorder, and its progression is positively associated with the number of senescent cells in the synovium of the joint. Senolytics have been used to slow or reverse the aging process, which is currently limited by off-target toxicity. Therapeutic efficacy can be achieved by enhancing the immune-mediated clearance of senescent cells. However, the surveillance of senescent cells by the immune system is often hindered by immunosuppressive factors within the inflammatory microenvironment. Herein, we constructed photoactivatable exosenolytics based on microphage-derived exosomes adorned with the gripper ligand aPD-L1 and aging cell-targeting ligands, encapsulating with a photosensitizer and NKG2D ligand activator for the precise antiaging treatment of OA. Exosenolytic-mediated photodynamic therapy can induce the recruitment of natural killer (NK) cells, enhance the gripping effect of NK cells to senescent fibroblast-like synoviocytes, and strengthen the immune system for clearance of senescent synovial cells by activating the cGAS-STING pathway. Importantly, exosenolytics selectively accumulated in senescent fibroblast-like synoviocytes in the inflamed joints of OA mice and effectively suppressed synovial inflammation and progression of OA. Exosenolytics employ an immunological conversion strategy to remodel the senescent immune microenvironment, offering a promising approach for aging immunotherapy.