DHA sustains frozen-cell-induced efferocytosis by mitigating endoplasmic reticulum stress to promote inflammation resolution and bone repair

Osteoporosis, a prevalent age-related condition, is associated with chronic inflammation and impaired bone repair, exacerbated by defective efferocytosis—the clearance of apoptotic cells (ACs) by macrophages. Therefore, enhancing the efferocytosis by apoptotic cell injection to reduce inflammation is a potential strategy for the treatment of osteoporosis. However, phagocytes experience metabolic stress such as endoplasmic reticulum (ER) stress during continuous ACs uptake, reflecting requirement for safe and effective solutions. To address this, we develop a novel therapy utilizing liquid nitrogen-frozen cells loaded with docosahexaenoic acid (DHA, FrozCell-DHA). In an ovariectomy (OVX)-induced mouse model of postmenopausal osteoporosis, FrozCell-DHA significantly enhance macrophage efferocytosis, alleviate inflammation, and reduce bone loss. Mechanistically, DHA reduces ER stress by activating the PPARγ pathway, driving continuous efferocytosis. These findings highlight FrozCell-DHA as a safe therapeutic approach, capable of restoring efferocytosis and promoting bone regeneration. Our study indicates the potential of FrozCell-DHA as a transformative therapy for osteoporosis, providing a promising proposal for bone repair and healthy aging.