Loss of skeletal integrity and decreased bone mass is a typical phenotype of aging. Senile osteoporosis seriously impaired bone structure and strength, which eventually led to skeleton fragile and bone fractures in aged people [1], [2], [3]. The impaired bone formation of the elderly required a long recovery time for bone fracture healing, resulting in increased mortality in elderly patients [4, 5]. Mounts of studies demonstrate aggravated senescence in the pool of bone marrow mesenchymal stem cells (BMSCs) and decline of osteogenic differentiation capacity of BMSCs during aging, leading to defect of bone formation in the aged skeleton. Traditional treatment of senile osteoporosis is supplementation of calcium and vitamin D and administration of anabolic drugs such as teriparatide or PTH. However, the therapeutic effect of current anabolic drugs is not sufficient to restore the balance between bone formation and resorption in a certain percentage of patients [6, 7]. Therefore, it is imperative to investigate the effective treatment for osteoporosis.

Cellular senescence is a special status characterized by irreversible cell cycle arrest and change of bio functions [8]. Accumulation of senescent cells is a hallmark of aging. The senescent cells not only lose normal cellular function but also disturb the function of neighbor cells by secreting high levels of inflammatory cytokines, immune modulators, growth factors, and proteases, which are termed senescence-associated secretory phenotype (SASP) [9]. The accumulation of senescent cells disturbs tissue homeostasis and impairs tissue regeneration, eventually resulting in age-related diseases [10], [11], [12], [13]. Recent findings demonstrate the senescence of BMSCs, which leads to a decline of osteogenesis and an abnormal increase of bone resorption, is the central etiology of age-related osteoporosis [14], [15], [16].

Recently, senolytics, the drugs selectively eliminate the senescent cells while performing no clearing effect on the normal ones, emerge as potential therapies for age-related diseases [17]. The results of several animal studies indeed verify potential therapeutic effect on age-related diseases including cardiovascular diseases, lung fibrosis, diabetes, hepatic steatosis, and neuropsychiatric disorders [18], [19], [20], [21], [22]. Recently, pilot studies have demonstrated that the elimination of senescent cells in the whole body by systematic administration of senolytic agents performs an obvious therapeutic effect on osteoporosis [3, 14]. However, these studies did not elucidate whether the senolytics function by eliminating senescent cells in the skeleton or other tissues. Furthermore, the dense structure and single blood supply of the skeleton obstructed the biodistribution of drugs to bone tissue [23]. The low biodistribution of senolytic drugs to bone tissue requires a high dose of agent and a long duration of treatment for osteoporosis, which may increase the side effect of senolytics [24]. Therefore, seeking an effective way to eliminate senescent cells in the skeleton is necessary for the application of senolytics in treating osteoporosis .

A tissue-targeted drug delivery system (DDS) is a direct and effective way to change the bioavailability and biodistribution of agents [25]. Thus, a bone-targeted drug delivery system is promising to control the biodistribution of senolytics to maximize the effective utilization of agents. In this study, we screened out quercetin as the ideal senolytic drug for senescent BMSCs and verified that the elimination of senescence facilitates the restoration of cellular functions of the senescent BMSCs. Then, we designed the bone-targeted liposomes loading senolytics to remove the senescent cells more efficiently in the bone of aged mice. Based on two aged mice models, we confirmed that bone-targeted delivery of quercetin efficiently eliminated senescent cells in bone and enhanced bone formation, suggesting bone-targeted elimination of senescent cells by quercetin is an effective treatment for senile osteoporosis.